Tuberculosis
Conditions
Brief summary
The purpose of this study was to evaluate the pharmacokinetics (PK), tolerability, and safety of once-weekly doses of rifapentine (RPT) and isoniazid (INH) in HIV-1-infected and HIV-1-uninfected pregnant and postpartum women with latent tuberculosis (TB).
Detailed description
TB is a major cause of illness and death in women of reproductive age. Pregnant and postpartum women with latent TB are at higher risk of developing active TB. This study evaluated the pharmacokinetics, tolerability, and safety of 12 once-weekly doses of RPT and INH in HIV-1-infected and HIV-1-uninfected pregnant and postpartum women with latent TB. This study enrolled HIV-1-infected and HIV-1-uninfected pregnant women with latent TB and their infants into two cohorts based on gestation. Cohort 1 participants were enrolled in their second trimester (greater than or equal to 14 to less than 28 weeks), and Cohort 2 participants were enrolled in their third trimester (greater than or equal to 28 to less than or equal to 34 weeks). All participants received 12 directly observed once-weekly doses of RPT, INH, and pyridoxine (vitamin B6) at study entry and at 11 weekly follow-up visits. Study researchers would perform an interim analysis to assess the PK of RPT during the study, and a dose adjustment could have been recommended based on this analysis. Study visits occurred at days 0-3, once a week through week 11, and once a month until 24 weeks after delivery. Visits would include physical examinations, obstetrical exams, and blood collection. Infants were followed monthly until 24 weeks after birth.
Interventions
900 mg of RPT
DRUGIsoniazid (INH)
900 mg of INH
DIETARY_SUPPLEMENTPyridoxine (vitamin B6)
25 mg to 100 mg of pyridoxine, based on the current local, national, or international dosing guidelines.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Age greater than or equal to 18 years, or minimum age of consent according to locally applicable laws or regulations at screening, verified per site standard operating procedures (SOPs); and able and willing to provide written informed consent for study at screening * At screening, evidence by ultrasound of a viable singleton pregnancy with an estimated gestational age at enrollment of greater than or equal to 14 weeks through less than or equal to 34 weeks as per screening ultrasound (see protocol for more information) * Had at least one of the following risk factors for TB: * Per participant report, the participant was a household contact (see NOTE below) of a known active pulmonary TB patient * Per medical records, confirmation of HIV-1 infection (see protocol for more information) and a single positive tuberculin skin test (TST) or interferon gamma release assay (IGRA) at any time in the past. If not available in medical record, perform at screening. NOTE: A household contact was defined as a person who currently lives or lived in the same dwelling unit and shares or shared the same housekeeping arrangements and who reported exposure within the past two years to an adult index case with pulmonary TB. Shared housekeeping arrangements were defined as sleeping under the same roof as the index TB case for at least seven consecutive days during the one month prior to the index case TB diagnosis. * Documentation of HIV-1 infection status, or confirmation of HIV-1 infection status (if unknown or undocumented). Confirmation of HIV-1 infection was defined as positive results from two samples (described in the protocol) collected at different time points. All samples tested must be whole blood, serum, or plasma. As this study was being conducted under an IND, all test methods should be FDA-approved, if available. If FDA-approved methods were not available, test methods should be verified according to Good Clinical Laboratory Practice (GCLP) and approved by the IMPAACT Laboratory Center. More information on this criterion was available in the protocol. * If HIV-1-infected, documented current prescription of efavirenz (EFV) + 2 nucleoside reverse transcriptase inhibitor (NRTI) regimen and reported taking regimen for at least two weeks prior to enrollment (regimens containing protease, integrase, or entry inhibitors were not permitted) * Documented laboratory values obtained within 14 days prior to enrollment: * Hemoglobin greater than or equal to 7.5 g/dL * White blood cell count greater than or equal to 1500 cells/mm\^3 * Alanine transaminase (ALT) less than 2.5 times the upper limit of normal (ULN) * Total bilirubin less than 1.6 times the ULN * Absolute neutrophil count (ANC) greater than or equal to 750 cells/mm\^3 * Platelet count greater than or equal to 100,000/mm\^3 * Per participant report at screening, intent to remain in the current geographical area of residence for the duration of the study * Per participant report at screening, able to swallow whole tablets * Per participant report, intention to keep the pregnancy * Per participant report, willingness to permit infant to participate in the study
Exclusion criteria
* Evidence of confirmed or probable active TB disease per World Health Organization (WHO) symptom screen and confirmation by Gene Xpert, shielded chest x-ray, or sputum sample * Participant report of personal history of INH- or rifampin-resistant, multi-drug resistant (MDR), or extensively drug-resistant (XDR) TB * Participant report of personal history of active TB in the past 2 years * Participant report of previous treatment for latent tuberculosis infection (LTBI) * Household contact (as defined above) with known active MDR or XDR TB disease * Known major fetal abnormality as detected on ultrasound * Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation * Known history of liver cirrhosis at any time prior to study entry * Per participant report and/or medical records, evidence of acute clinical hepatitis, such as a combination of abdominal pain, jaundice, dark urine, and/or light stools within 90 days prior to entry * Participant report and/or medical records of peripheral neuropathy Grade 2 or higher within 90 days prior to entry * Current use or history of active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements * Participant report and/or clinical evidence of porphyria * Any other condition that, in the opinion of the investigator of record (IoR)/designee, would preclude informed consent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives, including taking the study medication * Planned or current participation in an interventional drug study * Current use of any prohibited or precautionary medications (see protocol for more information), including didanosine (DDI) or stavudine (D4T)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Clearance Relative to Bioavailability (CL/F) for Rifapentine (RPT) for Intensive and Sparse PK | Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose). | PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Calculated an average CL for all women in the 2nd trimester (cohort I) and all women in the 3rd trimester (cohort II) |
| Clearance Relative to Bioavailability (CLmet/F) for Desacetyl Rifapentine (Des-RPT) | Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose). | PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption and a separate compartment for metabolite formation * Estimated a single des-RPT CLmet/F for the whole population Note: that the mean stated below is actually the value that is obtained from a population analysis and represents a population estimate with the relative standard error |
| Absorption Rate Constant (ka) for Rifapentine (RPT) | Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose). | PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Estimated the transit compartment rate constant (ktr), which is synonymous with the absorption constant (ka), for the whole population Note that the mean stated below is actually the value that is obtained from a population analysis and represents a population estimate |
| Volume of Distribution Relative to Bioavailability (Vc/F) for Rifapentine (RPT) | Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose). | PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Estimated a single RPT Vc/F for for the whole population Note: that the mean stated below is actually the value that is obtained from a population analysis and represents a population estimate with the relative standard error |
| Incidence of Related Serious Adverse Events (SAEs) in Pregnant and Postpartum Women Taking Once-weekly RPT + INH | Measured from entry through participants' last study visit at 24 weeks after delivery | At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used. |
| Percentage of Participants With Grade 2 Adverse Events (AEs) Judged to be Related to Study Drug Regimen | Measured from study entry through participants' last study visit at 24 weeks after delivery | At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) and were used. |
| Percentage of Participants With All Grade 3 and 4 AEs | Measured from study entry through participants' last study visit at 24 weeks after delivery | At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used. |
| Percentage of Participants With All Serious AEs | Measured from study entry through participants' last study visit at 24 weeks after delivery | At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used. |
| Percentage of Participants With All AEs Leading to Permanent Discontinuation of Study Drug Regimen (i.e., RPT, INH, and Pyridoxine) | Measured from study entry through participants' last study treatment dispensation (approximately for 12 weeks) | At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used. |
| Percentage of Participants With Related Serious Adverse Events (AEs) in Infants Born to Women Taking Once-weekly RPT + INH | Measured from birth through infants' last study visit at 24 weeks after birth | At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Infants With Active TB up to 24 Weeks of Life | Measured from birth through participants' last study visit at 24 weeks after delivery | Based on site-specified confirmatory TB test. If women and infants were diagnosed with active TB during study they would be referred to local care for TB management and treatment. |
| Clearance (CL/F) of INH | Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose). | PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with 2 mixtures to characterize subpopulations based on acetylation status * Estimated a separate INH CL/F based on acetylation status (fast, slow) |
| Clearance Relative to Bioavailability (CL/F) for Rifapentine (RPT) | Data used in the population PK analysis for postpartum women included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose). | PK parameters from postpartum women were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Calculated an average CL for all post-partum individuals |
| Volume of Distribution of INH | Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose). | PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). • Estimated a single INH Vc/F for the whole population |
| Absorption (ka) of INH | Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose). | PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). • Estimated a single absorption rate constant (ka) for the whole population |
| Area Under the Curve From 0 to 24 Hours (AUC0-24) for RPT and Area Under the Curve From 0 to 24 Hours (AUC0-24) for Des-RPT Pregnant Women in 2nd and 3rd Trimester | Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose). | PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Obtained AUC by model-based integration |
| Maximum Concentration (Cmax) for RPT Maximum Concentration (Cmax) for Des-RPT Pregnant Women in 2nd and 3rd Trimester | Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose). | PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Obtained Cmax by model-based estimation |
| Maximum Concentration (Cmin) for RPT and Maximum Concentration (Cmin) for Des-RPT Pregnant Women in 2nd and 3rd Trimester | Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose). | PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Obtained Cmin by model-based estimation |
| Cord Blood Concentrations of Rifapentine (RPT) Among Infants | at delivery - (within 3 days of life for infants) | Cord blood concentrations were summarized using using R (version 3.5.1). |
| Plasma Concentrations of Rifapentine (RPT) Among Infants | at delivery - (within 3 days of life for infants). | Plasma concentrations were summarized using using R (version 3.5.1). |
| Cord Blood Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants | at delivery (within 3 days of life for infants). | Cord blood concentrations were summarized using using R (version 3.5.1). |
| Plasma Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants | at delivery - (within 3 days of life for infants). | Plasma blood concentrations were summarized using using R (version 3.5.1). |
| Number of Participants With Discontinuation of Study Drug Due to Intolerance (Tolerability of Study Drug Regimen - i.e., RPT, INH, and Pyridoxine) | Measured from study entry through participants' last study visit at 24 weeks after delivery | At entry and follow-up, all lab results, sign and symptoms, and diagnoses will be recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that result in discontinuation of study drug regimen, and that meet criteria for EAE reporting will be further evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used. |
| Number of Mothers With Active TB up to 24 Weeks Postpartum | Measured from study entry through participants' last study visit at 24 weeks after delivery | Based on site-specified confirmatory TB test. If women and infants were diagnosed with active TB during study they would be referred to local care for TB management and treatment. |
Countries
Haiti, Kenya, Malawi, Thailand, Zimbabwe
Participant flow
Recruitment details
The first participant was enrolled on March 13, 2017 and accrual was completed on June 12, 2018 across the following sites: Siriraj Hospital, Mahidol University NIC (CRS 5115), Kenya Medical Research Institute/Walter Reed Project (CRS 5121), Malawi (CRS 12001), the Les Centres GHESKIO INLR (CRS 30022), and Harare Family Care (CRS 31890).
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) Participants received 12 directly observed once-weekly doses of RPT, INH, and pyridoxine (vitamin B6) at study entry and at 11 weekly follow-up visits. | 25 |
| Cohort 2 (Pregnant Women Enrolled in the Third Trimester) Participants received 12 directly observed once-weekly doses of RPT, INH, and pyridoxine (vitamin B6) at study entry and at 11 weekly follow-up visits. | 25 |
| Total | 50 |
Baseline characteristics
| Characteristic | Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Total | Cohort 2 (Pregnant Women Enrolled in the Third Trimester) |
|---|---|---|---|
| Absolute CD4 count | 586 cells/mm^3 | 510 cells/mm^3 | 489 cells/mm^3 |
| Age, Categorical <=18 years | 1 Participants | 4 Participants | 3 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 24 Participants | 46 Participants | 22 Participants |
| Age, Continuous | 26 years | 27 years | 27 years |
| Gestational Age at Screening | 20 weeks | 26 weeks | 30 weeks |
| HIV-1 status HIV-1 infected | 10 Participants | 20 Participants | 10 Participants |
| HIV-1 status HIV-1 uninfected | 15 Participants | 30 Participants | 15 Participants |
| Mid-upper arm circumference (MUAC) | 27 centimeters | 27 centimeters | 27 centimeters |
| Prothrombin Time result | 10 seconds | 10 seconds | 11 seconds |
| Race/Ethnicity, Customized Asian, Pacific Islander | 1 Participants | 3 Participants | 2 Participants |
| Race/Ethnicity, Customized Black Non-Hispanic | 24 Participants | 47 Participants | 23 Participants |
| Region of Enrollment Haiti | 11 participants | 16 participants | 5 participants |
| Region of Enrollment Kenya | 2 participants | 7 participants | 5 participants |
| Region of Enrollment Malawi | 2 participants | 3 participants | 1 participants |
| Region of Enrollment Thailand | 1 participants | 3 participants | 2 participants |
| Region of Enrollment Zimbabwe | 9 participants | 21 participants | 12 participants |
| Serum glutamic-oxaloacetic transaminase (SGOT) | 21 units/L | 21 units/L | 21 units/L |
| Serum glutamic pyruvic transaminase (SGPT) | 17 units/L | 15 units/L | 14 units/L |
| Sex: Female, Male Female | 25 Participants | 50 Participants | 25 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Weight | 59 kilograms | 61 kilograms | 61 kilograms |
| World Health Organization (WHO) clinical stage Clinical Stage 1 | 10 Participants | 20 Participants | 10 Participants |
| World Health Organization (WHO) clinical stage Clinical Stage 2 | 0 Participants | 0 Participants | 0 Participants |
| World Health Organization (WHO) clinical stage Clinical Stage 3 | 0 Participants | 0 Participants | 0 Participants |
| World Health Organization (WHO) clinical stage Clinical Stage 4 | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 25 | 0 / 25 |
| other Total, other adverse events | 24 / 25 | 25 / 25 |
| serious Total, serious adverse events | 2 / 25 | 3 / 25 |
Outcome results
Primary
Absorption Rate Constant (ka) for Rifapentine (RPT)
PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Estimated the transit compartment rate constant (ktr), which is synonymous with the absorption constant (ka), for the whole population Note that the mean stated below is actually the value that is obtained from a population analysis and represents a population estimate
Time frame: Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).
Population: All participants with intensive and sparse PK results at all doses in all stages of pregnancy were used for analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Absorption Rate Constant (ka) for Rifapentine (RPT) | 1.43 hr-1 |
Primary
Clearance Relative to Bioavailability (CL/F) for Rifapentine (RPT) for Intensive and Sparse PK
PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Calculated an average CL for all women in the 2nd trimester (cohort I) and all women in the 3rd trimester (cohort II)
Time frame: Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).
Population: All participants with intensive and sparse PK results at all doses in all stages of pregnancy were used for analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Clearance Relative to Bioavailability (CL/F) for Rifapentine (RPT) for Intensive and Sparse PK | 1.4 L/hr |
| Cohort 2 (Pregnant Women Enrolled in the Third Trimester) | Clearance Relative to Bioavailability (CL/F) for Rifapentine (RPT) for Intensive and Sparse PK | 1.50 L/hr |
Primary
Clearance Relative to Bioavailability (CLmet/F) for Desacetyl Rifapentine (Des-RPT)
PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption and a separate compartment for metabolite formation * Estimated a single des-RPT CLmet/F for the whole population Note: that the mean stated below is actually the value that is obtained from a population analysis and represents a population estimate with the relative standard error
Time frame: Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).
Population: All participants with intensive and sparse PK results at all doses in all stages of pregnancy were used for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Clearance Relative to Bioavailability (CLmet/F) for Desacetyl Rifapentine (Des-RPT) | 2.82 L/hr | Standard Error 7 |
Primary
Incidence of Related Serious Adverse Events (SAEs) in Pregnant and Postpartum Women Taking Once-weekly RPT + INH
At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used.
Time frame: Measured from entry through participants' last study visit at 24 weeks after delivery
Population: All participants enrolled in the study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Incidence of Related Serious Adverse Events (SAEs) in Pregnant and Postpartum Women Taking Once-weekly RPT + INH | 0 Participants |
| Cohort 2 (Pregnant Women Enrolled in the Third Trimester) | Incidence of Related Serious Adverse Events (SAEs) in Pregnant and Postpartum Women Taking Once-weekly RPT + INH | 0 Participants |
Primary
Percentage of Participants With All AEs Leading to Permanent Discontinuation of Study Drug Regimen (i.e., RPT, INH, and Pyridoxine)
At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used.
Time frame: Measured from study entry through participants' last study treatment dispensation (approximately for 12 weeks)
Population: All participants enrolled on the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Percentage of Participants With All AEs Leading to Permanent Discontinuation of Study Drug Regimen (i.e., RPT, INH, and Pyridoxine) | 0 percent of participants |
| Cohort 2 (Pregnant Women Enrolled in the Third Trimester) | Percentage of Participants With All AEs Leading to Permanent Discontinuation of Study Drug Regimen (i.e., RPT, INH, and Pyridoxine) | 0 percent of participants |
Primary
Percentage of Participants With All Grade 3 and 4 AEs
At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used.
Time frame: Measured from study entry through participants' last study visit at 24 weeks after delivery
Population: All participants enrolled on the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Percentage of Participants With All Grade 3 and 4 AEs | 20 percent of participants |
| Cohort 2 (Pregnant Women Enrolled in the Third Trimester) | Percentage of Participants With All Grade 3 and 4 AEs | 16 percent of participants |
Primary
Percentage of Participants With All Serious AEs
At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used.
Time frame: Measured from study entry through participants' last study visit at 24 weeks after delivery
Population: All participants enrolled on the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Percentage of Participants With All Serious AEs | 8 percent of participants |
| Cohort 2 (Pregnant Women Enrolled in the Third Trimester) | Percentage of Participants With All Serious AEs | 12 percent of participants |
Primary
Percentage of Participants With Grade 2 Adverse Events (AEs) Judged to be Related to Study Drug Regimen
At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) and were used.
Time frame: Measured from study entry through participants' last study visit at 24 weeks after delivery
Population: All participant enrolled on the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Percentage of Participants With Grade 2 Adverse Events (AEs) Judged to be Related to Study Drug Regimen | 4 percent of participants |
| Cohort 2 (Pregnant Women Enrolled in the Third Trimester) | Percentage of Participants With Grade 2 Adverse Events (AEs) Judged to be Related to Study Drug Regimen | 0 percent of participants |
Primary
Percentage of Participants With Related Serious Adverse Events (AEs) in Infants Born to Women Taking Once-weekly RPT + INH
At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used.
Time frame: Measured from birth through infants' last study visit at 24 weeks after birth
Population: For the 49 live born infants to the women enrolled on the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Percentage of Participants With Related Serious Adverse Events (AEs) in Infants Born to Women Taking Once-weekly RPT + INH | 0 percent of participants |
| Cohort 2 (Pregnant Women Enrolled in the Third Trimester) | Percentage of Participants With Related Serious Adverse Events (AEs) in Infants Born to Women Taking Once-weekly RPT + INH | 0 percent of participants |
Primary
Volume of Distribution Relative to Bioavailability (Vc/F) for Rifapentine (RPT)
PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Estimated a single RPT Vc/F for for the whole population Note: that the mean stated below is actually the value that is obtained from a population analysis and represents a population estimate with the relative standard error
Time frame: Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).
Population: All participants with intensive and sparse PK results at all doses in all stages of pregnancy were used for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Volume of Distribution Relative to Bioavailability (Vc/F) for Rifapentine (RPT) | 30.1 L | Standard Error 5 |
Secondary
Absorption (ka) of INH
PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). • Estimated a single absorption rate constant (ka) for the whole population
Time frame: Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).
Population: All participants with intensive and sparse PK results at all doses in all stages of pregnancy were used for analysis Note: the mean reported below is actually the value obtained from a population analysis and represents a population estimate with relative standard error
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Absorption (ka) of INH | 1.74 hr-1 | Standard Error 49 |
Secondary
Area Under the Curve From 0 to 24 Hours (AUC0-24) for RPT and Area Under the Curve From 0 to 24 Hours (AUC0-24) for Des-RPT Pregnant Women in 2nd and 3rd Trimester
PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Obtained AUC by model-based integration
Time frame: Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).
Population: All participants with intensive and sparse PK results for RPT at all doses in all stages of pregnancy were used for analysis
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Area Under the Curve From 0 to 24 Hours (AUC0-24) for RPT and Area Under the Curve From 0 to 24 Hours (AUC0-24) for Des-RPT Pregnant Women in 2nd and 3rd Trimester | AUC (0-24) for RPT | 424.7 hour*mg/L |
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Area Under the Curve From 0 to 24 Hours (AUC0-24) for RPT and Area Under the Curve From 0 to 24 Hours (AUC0-24) for Des-RPT Pregnant Women in 2nd and 3rd Trimester | AUC (0-24) for des-RPT | 158.7 hour*mg/L |
| Cohort 2 (Pregnant Women Enrolled in the Third Trimester) | Area Under the Curve From 0 to 24 Hours (AUC0-24) for RPT and Area Under the Curve From 0 to 24 Hours (AUC0-24) for Des-RPT Pregnant Women in 2nd and 3rd Trimester | AUC (0-24) for des-RPT | 153.7 hour*mg/L |
| Cohort 2 (Pregnant Women Enrolled in the Third Trimester) | Area Under the Curve From 0 to 24 Hours (AUC0-24) for RPT and Area Under the Curve From 0 to 24 Hours (AUC0-24) for Des-RPT Pregnant Women in 2nd and 3rd Trimester | AUC (0-24) for RPT | 406.8 hour*mg/L |
Secondary
Clearance (CL/F) of INH
PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with 2 mixtures to characterize subpopulations based on acetylation status * Estimated a separate INH CL/F based on acetylation status (fast, slow)
Time frame: Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).
Population: All participants with intensive and sparse PK results at all doses in all stages of pregnancy were used for analysis Note: the mean reported below is actually the value obtained from a population analysis and represents a population estimate with relative standard error
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Clearance (CL/F) of INH | CL/F (slow acetylators) | 8.98 L/hr | Standard Error 47 |
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Clearance (CL/F) of INH | CL/F (fast acetylators) | 32.7 L/hr | Standard Error 10 |
Secondary
Clearance Relative to Bioavailability (CL/F) for Rifapentine (RPT)
PK parameters from postpartum women were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Calculated an average CL for all post-partum individuals
Time frame: Data used in the population PK analysis for postpartum women included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).
Population: All participants with intensive and sparse PK results at all doses postpartum were used for analysis.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Clearance Relative to Bioavailability (CL/F) for Rifapentine (RPT) | 1.64 L/hr |
Secondary
Cord Blood Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants
Cord blood concentrations were summarized using using R (version 3.5.1).
Time frame: at delivery (within 3 days of life for infants).
Population: All infants with available concentrations born to women on the study
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Cord Blood Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants | 3.24 mcg/mL |
Secondary
Cord Blood Concentrations of Rifapentine (RPT) Among Infants
Cord blood concentrations were summarized using using R (version 3.5.1).
Time frame: at delivery - (within 3 days of life for infants)
Population: All infants with available concentration data born to women on the study
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Cord Blood Concentrations of Rifapentine (RPT) Among Infants | 2.97 mcg/mL |
Secondary
Maximum Concentration (Cmax) for RPT Maximum Concentration (Cmax) for Des-RPT Pregnant Women in 2nd and 3rd Trimester
PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Obtained Cmax by model-based estimation
Time frame: Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).
Population: All participants with intensive and sparse PK results for RPT at all doses in all stages of pregnancy were used for analysis.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Maximum Concentration (Cmax) for RPT Maximum Concentration (Cmax) for Des-RPT Pregnant Women in 2nd and 3rd Trimester | Cmax for des-RPT | 8.76 mg/L |
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Maximum Concentration (Cmax) for RPT Maximum Concentration (Cmax) for Des-RPT Pregnant Women in 2nd and 3rd Trimester | Cmax for RPT | 30.2 mg/L |
| Cohort 2 (Pregnant Women Enrolled in the Third Trimester) | Maximum Concentration (Cmax) for RPT Maximum Concentration (Cmax) for Des-RPT Pregnant Women in 2nd and 3rd Trimester | Cmax for des-RPT | 8.50 mg/L |
| Cohort 2 (Pregnant Women Enrolled in the Third Trimester) | Maximum Concentration (Cmax) for RPT Maximum Concentration (Cmax) for Des-RPT Pregnant Women in 2nd and 3rd Trimester | Cmax for RPT | 28.6 mg/L |
Secondary
Maximum Concentration (Cmin) for RPT and Maximum Concentration (Cmin) for Des-RPT Pregnant Women in 2nd and 3rd Trimester
PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Obtained Cmin by model-based estimation
Time frame: Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).
Population: All participants with intensive and sparse PK results for RPT at all doses in all stages of pregnancy were used for analysis.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Maximum Concentration (Cmin) for RPT and Maximum Concentration (Cmin) for Des-RPT Pregnant Women in 2nd and 3rd Trimester | Cmin for RPT | 1.45 mg/L |
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Maximum Concentration (Cmin) for RPT and Maximum Concentration (Cmin) for Des-RPT Pregnant Women in 2nd and 3rd Trimester | Cmin for des-RPT | 1.06 mg/L |
| Cohort 2 (Pregnant Women Enrolled in the Third Trimester) | Maximum Concentration (Cmin) for RPT and Maximum Concentration (Cmin) for Des-RPT Pregnant Women in 2nd and 3rd Trimester | Cmin for RPT | 1.58 mg/L |
| Cohort 2 (Pregnant Women Enrolled in the Third Trimester) | Maximum Concentration (Cmin) for RPT and Maximum Concentration (Cmin) for Des-RPT Pregnant Women in 2nd and 3rd Trimester | Cmin for des-RPT | 1.20 mg/L |
Secondary
Number of Infants With Active TB up to 24 Weeks of Life
Based on site-specified confirmatory TB test. If women and infants were diagnosed with active TB during study they would be referred to local care for TB management and treatment.
Time frame: Measured from birth through participants' last study visit at 24 weeks after delivery
Population: All live born infants enrolled on the study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Number of Infants With Active TB up to 24 Weeks of Life | 0 Participants |
| Cohort 2 (Pregnant Women Enrolled in the Third Trimester) | Number of Infants With Active TB up to 24 Weeks of Life | 0 Participants |
Secondary
Number of Mothers With Active TB up to 24 Weeks Postpartum
Based on site-specified confirmatory TB test. If women and infants were diagnosed with active TB during study they would be referred to local care for TB management and treatment.
Time frame: Measured from study entry through participants' last study visit at 24 weeks after delivery
Population: All participants enrolled on the study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Number of Mothers With Active TB up to 24 Weeks Postpartum | 0 Participants |
| Cohort 2 (Pregnant Women Enrolled in the Third Trimester) | Number of Mothers With Active TB up to 24 Weeks Postpartum | 0 Participants |
Secondary
Number of Participants With Discontinuation of Study Drug Due to Intolerance (Tolerability of Study Drug Regimen - i.e., RPT, INH, and Pyridoxine)
At entry and follow-up, all lab results, sign and symptoms, and diagnoses will be recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that result in discontinuation of study drug regimen, and that meet criteria for EAE reporting will be further evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used.
Time frame: Measured from study entry through participants' last study visit at 24 weeks after delivery
Population: All participants enrolled on the study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Number of Participants With Discontinuation of Study Drug Due to Intolerance (Tolerability of Study Drug Regimen - i.e., RPT, INH, and Pyridoxine) | 0 Participants |
| Cohort 2 (Pregnant Women Enrolled in the Third Trimester) | Number of Participants With Discontinuation of Study Drug Due to Intolerance (Tolerability of Study Drug Regimen - i.e., RPT, INH, and Pyridoxine) | 0 Participants |
Secondary
Plasma Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants
Plasma blood concentrations were summarized using using R (version 3.5.1).
Time frame: at delivery - (within 3 days of life for infants).
Population: All infants with available concentrations born to women on the study
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Plasma Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants | 5.31 mcg/mL |
Secondary
Plasma Concentrations of Rifapentine (RPT) Among Infants
Plasma concentrations were summarized using using R (version 3.5.1).
Time frame: at delivery - (within 3 days of life for infants).
Population: All infants with available concentrations born to women on the study
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Plasma Concentrations of Rifapentine (RPT) Among Infants | 2.47 mcg/mL |
Secondary
Volume of Distribution of INH
PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). • Estimated a single INH Vc/F for the whole population
Time frame: Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).
Population: All participants with intensive and sparse PK results at all doses in all stages of pregnancy were used for analysis Note: the mean reported below is actually the value obtained from a population analysis and represents a population estimate with relative standard error
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Pregnant Women Enrolled in the Second Trimester) | Volume of Distribution of INH | 107 L | Standard Error 12 |