Evaluating PK, Tolerability, and Safety of Rifapentine and Isoniazid in Pregnant and Postpartum Women

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT02651259
• Collaborator: (none)
• Enrollment: 50
• Locations: 5
• Arms: 2
• Actual Duration (Months): 24.9
• Patients Per Site: 10
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Tuberculosis	Drug: Rifapentine (RPT); Drug: Isoniazid (INH); Dietary Supplement: Pyridoxine (vitamin B6)	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Trial of the Pharmacokinetics, Tolerability, and Safety of Once-Weekly Rifapentine and Isoniazid in HIV-1-infected and HIV-1-uninfected Pregnant and Postpartum Women With Latent Tuberculosis Infection
• Actual Study Start Date: Mar 13, 2017
• Actual Primary Completion Date: Apr 10, 2019
• Actual Study Completion Date: Apr 10, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: Rifapentine (RPT); 900 mg of RPT; Other Names: Rifamycin ; Drug: Isoniazid (INH); 900 mg of INH; Other Names: isonicotinyl hydrazine, ; Dietary Supplement: Pyridoxine (vitamin B6); 25 mg to 100 mg of pyridoxine, based on the current local, national, or international dosing guidelines.; Other Names: Vitamin B6
Experimental: 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.	Drug: Rifapentine (RPT); 900 mg of RPT; Other Names: Rifamycin ; Drug: Isoniazid (INH); 900 mg of INH; Other Names: isonicotinyl hydrazine, ; Dietary Supplement: Pyridoxine (vitamin B6); 25 mg to 100 mg of pyridoxine, based on the current local, national, or international dosing guidelines.; Other Names: Vitamin B6

Outcome Measures

Primary Outcome Measures

1. 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)

2. 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

3. 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

4. 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

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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 Outcome Measures

1. 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

2. 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

3. 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

4. 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

5. 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).

6. 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).

7. 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).

8. 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).

9. 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.

10. 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.

11. 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.

12. 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)

13. 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

14. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts 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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS	Port-au-Prince		Haiti	HT-6110
2	Kenya Medical Research Institute / Walter Reed Project Clinical Research Center, Kericho CRS	Kericho		Kenya	20200
3	Malawi CRS	Lilongwe	Central Malawi	Malawi
4	Siriraj Hospital ,Mahidol University NICHD CRS	Bangkok	Bangkoknoi	Thailand	10700
5	Harare Family Care CRS	Harare		Zimbabwe

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Study Chair: Jyoti S. Mathad, MD, MSc, Weill Medical College of Cornell University

Study Documents (Full-Text)

• Study Protocol - Nov 10, 2015
• Statistical Analysis Plan: Final Safety Statistical Analysis Plan - Jun 26, 2019
• Statistical Analysis Plan: Final PK Statistical Analysis Plan - Mar 31, 2020

More Information

Additional Information:

• Severity and laboratory tests will be graded per the DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 2.0(dated November 2014 available on the RSC website)
• Requirements, definitions and methods for expedited reporting of adverse events (AEs) are outlined in Version 2.0 of the DAIDS EAE Manual

Publications

None provided.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT02651259
• Other Study ID Numbers: IMPAACT 2001; 12026
• First Posted: Jan 8, 2016
• Last Update Posted: Nov 4, 2021
• Last Verified: May 1, 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Tuberculosis; Vitamins; Pyridoxine; Pyridoxal; Vitamin B 6; Vitamin B Complex; Isoniazid; Rifapentine; Rifamycins; Hydrazine

Study Results

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).

Arm/Group Title	Cohort 1 (Pregnant Women Enrolled in the Second Trimester)	Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	25	25
COMPLETED	25	25
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Cohort 1 (Pregnant Women Enrolled in the Second Trimester)	Cohort 2 (Pregnant Women Enrolled in the Third Trimester)	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	25	25	50
Age (Count of Participants)
<=18 years	1 4%	3 12%	4 8%
Between 18 and 65 years	24 96%	22 88%	46 92%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	26	27	27
Sex: Female, Male (Count of Participants)
Female	25 100%	25 100%	50 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
Black Non-Hispanic	24 96%	23 92%	47 94%
Asian, Pacific Islander	1 4%	2 8%	3 6%
Region of Enrollment (participants) [Number]
Haiti	11 44%	5 20%	16 32%
Malawi	2 8%	1 4%	3 6%
Zimbabwe	9 36%	12 48%	21 42%
Kenya	2 8%	5 20%	7 14%
Thailand	1 4%	2 8%	3 6%
HIV-1 status (Count of Participants)
HIV-1 uninfected	15 60%	15 60%	30 60%
HIV-1 infected	10 40%	10 40%	20 40%
Absolute CD4 count (cells/mm^3) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [cells/mm^3]	586	489	510
World Health Organization (WHO) clinical stage (Count of Participants)
Clinical Stage 1	10 40%	10 40%	20 40%
Clinical Stage 2	0 0%	0 0%	0 0%
Clinical Stage 3	0 0%	0 0%	0 0%
Clinical Stage 4	0 0%	0 0%	0 0%
Weight (kilograms) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kilograms]	59	61	61
Gestational Age at Screening (weeks) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [weeks]	20	30	26
Mid-upper arm circumference (MUAC) (centimeters) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [centimeters]	27	27	27
Serum glutamic-oxaloacetic transaminase (SGOT) (units/L) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units/L]	21	21	21
Serum glutamic pyruvic transaminase (SGPT) (units/L) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units/L]	17	14	15
Prothrombin Time result (seconds) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [seconds]	10	11	10

Outcome Measures

1. Primary Outcome

Title	Clearance Relative to Bioavailability (CL/F) for Rifapentine (RPT) for Intensive and Sparse PK
Description	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).

Outcome Measure Data

Analysis Population Description

All participants with intensive and sparse PK results at all doses in all stages of pregnancy were used for analysis.

Arm/Group Title	Cohort 1 (Pregnant Women Enrolled in the Second Trimester)	Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Arm/Group Description	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.	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.
Measure Participants	24	25
Mean (Inter-Quartile Range) [L/hr]	1.4	1.50

2. Primary Outcome

Title	Clearance Relative to Bioavailability (CLmet/F) for Desacetyl Rifapentine (Des-RPT)
Description	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).

Outcome Measure Data

Analysis Population Description

All participants with intensive and sparse PK results at all doses in all stages of pregnancy were used for analysis.

Arm/Group Title	All Cohorts
Arm/Group Description	Combined for all women in Second and Third Trimester of pregnancy
Measure Participants	49
Mean (Standard Error) [L/hr]	2.82 (7)

3. Primary Outcome

Title	Absorption Rate Constant (ka) for Rifapentine (RPT)
Description	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).

Outcome Measure Data

Analysis Population Description

All participants with intensive and sparse PK results at all doses in all stages of pregnancy were used for analysis.

Arm/Group Title	All Cohorts
Arm/Group Description	Combined for all women in Second and Third Trimester of pregnancy
Measure Participants	49
Mean (Standard Error) [hr-1]	1.43 (NA)

4. Primary Outcome

Title	Volume of Distribution Relative to Bioavailability (Vc/F) for Rifapentine (RPT)
Description	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).

Outcome Measure Data

Analysis Population Description

All participants with intensive and sparse PK results at all doses in all stages of pregnancy were used for analysis.

Arm/Group Title	All Cohorts
Arm/Group Description	Combined for all women in Second and Third Trimester of pregnancy
Measure Participants	49
Mean (Standard Error) [L]	30.1 (5)

5. Primary Outcome

Title	Incidence of Related Serious Adverse Events (SAEs) in Pregnant and Postpartum Women Taking Once-weekly RPT + INH
Description	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

Outcome Measure Data

Analysis Population Description

All participants enrolled in the study

Arm/Group Title	Cohort 1 (Pregnant Women Enrolled in the Second Trimester)	Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Arm/Group Description	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.	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.
Measure Participants	25	25
Count of Participants [Participants]	0 0%	0 0%

6. Primary Outcome

Title	Percentage of Participants With Grade 2 Adverse Events (AEs) Judged to be Related to Study Drug Regimen
Description	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

Outcome Measure Data

Analysis Population Description

All participant enrolled on the study

Arm/Group Title	Cohort 1 (Pregnant Women Enrolled in the Second Trimester)	Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Arm/Group Description	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.	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.
Measure Participants	25	25
Number (95% Confidence Interval) [percent of participants]	4 16%	0 0%

7. Primary Outcome

Title	Percentage of Participants With All Grade 3 and 4 AEs
Description	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

Outcome Measure Data

Analysis Population Description

All participants enrolled on the study

Arm/Group Title	Cohort 1 (Pregnant Women Enrolled in the Second Trimester)	Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Arm/Group Description	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.	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.
Measure Participants	25	25
Number (95% Confidence Interval) [percent of participants]	20 80%	16 64%

8. Primary Outcome

Title	Percentage of Participants With All Serious AEs
Description	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

Outcome Measure Data

Analysis Population Description

All participants enrolled on the study

Arm/Group Title	Cohort 1 (Pregnant Women Enrolled in the Second Trimester)	Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Arm/Group Description	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.	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.
Measure Participants	25	25
Number (95% Confidence Interval) [percent of participants]	8 32%	12 48%

9. Primary Outcome

Title	Percentage of Participants With All AEs Leading to Permanent Discontinuation of Study Drug Regimen (i.e., RPT, INH, and Pyridoxine)
Description	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)

Outcome Measure Data

Analysis Population Description

All participants enrolled on the study

Arm/Group Title	Cohort 1 (Pregnant Women Enrolled in the Second Trimester)	Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Arm/Group Description	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.	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.
Measure Participants	25	25
Number (95% Confidence Interval) [percent of participants]	0 0%	0 0%

10. Primary Outcome

Title	Percentage of Participants With Related Serious Adverse Events (AEs) in Infants Born to Women Taking Once-weekly RPT + INH
Description	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

Outcome Measure Data

Analysis Population Description

For the 49 live born infants to the women enrolled on the study

Arm/Group Title	Cohort 1 (Infants Born to Women Enrolled in Second Trimester)	Cohort 2 (Infants Born to Women Enrolled in Third Trimester)
Arm/Group Description	Infants born to women who received 12 directly observed once-weekly doses of RPT, INH, and pyridoxine (vitamin B6) at study entry and at 11 weekly follow-up visits.	Infants born to women who received 12 directly observed once-weekly doses of RPT, INH, and pyridoxine (vitamin B6) at study entry and at 11 weekly follow-up visits.
Measure Participants	24	25
Number (95% Confidence Interval) [percent of participants]	0 0%	0 0%

11. Secondary Outcome

Title	Clearance Relative to Bioavailability (CL/F) for Rifapentine (RPT)
Description	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).

Outcome Measure Data

Analysis Population Description

All participants with intensive and sparse PK results at all doses postpartum were used for analysis.

Arm/Group Title	All Cohorts
Arm/Group Description	All postpartum women
Measure Participants	22
Mean (Inter-Quartile Range) [L/hr]	1.64

12. Secondary Outcome

Title	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
Description	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).

Outcome Measure Data

Analysis Population Description

All participants with intensive and sparse PK results for RPT at all doses in all stages of pregnancy were used for analysis

Arm/Group Title	Cohort 1 (Pregnant Women Enrolled in the Second Trimester)	Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Arm/Group Description	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.	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.
Measure Participants	22	19
AUC (0-24) for RPT	424.7	406.8
AUC (0-24) for des-RPT	158.7	153.7

13. Secondary Outcome

Title	Maximum Concentration (Cmax) for RPT Maximum Concentration (Cmax) for Des-RPT Pregnant Women in 2nd and 3rd Trimester
Description	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).

Outcome Measure Data

Analysis Population Description

All participants with intensive and sparse PK results for RPT at all doses in all stages of pregnancy were used for analysis.

Arm/Group Title	Cohort 1 (Pregnant Women Enrolled in the Second Trimester)	Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Arm/Group Description	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.	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.
Measure Participants	22	19
Cmax for RPT	30.2	28.6
Cmax for des-RPT	8.76	8.50

14. Secondary Outcome

Title	Maximum Concentration (Cmin) for RPT and Maximum Concentration (Cmin) for Des-RPT Pregnant Women in 2nd and 3rd Trimester
Description	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).

Outcome Measure Data

Analysis Population Description

All participants with intensive and sparse PK results for RPT at all doses in all stages of pregnancy were used for analysis.

Arm/Group Title	Cohort 1 (Pregnant Women Enrolled in the Second Trimester)	Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Arm/Group Description	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.	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.
Measure Participants	23	25
Cmin for RPT	1.45	1.58
Cmin for des-RPT	1.06	1.20

15. Secondary Outcome

Title	Cord Blood Concentrations of Rifapentine (RPT) Among Infants
Description	Cord blood concentrations were summarized using using R (version 3.5.1).
Time Frame	at delivery - (within 3 days of life for infants)

Outcome Measure Data

Analysis Population Description

All infants with available concentration data born to women on the study

Arm/Group Title	All Cohorts
Arm/Group Description	Combined for all infants born to women in Second and Third Trimester of pregnancy
Measure Participants	5
Mean (Inter-Quartile Range) [mcg/mL]	2.97

16. Secondary Outcome

Title	Plasma Concentrations of Rifapentine (RPT) Among Infants
Description	Plasma concentrations were summarized using using R (version 3.5.1).
Time Frame	at delivery - (within 3 days of life for infants).

Outcome Measure Data

Analysis Population Description

All infants with available concentrations born to women on the study

Arm/Group Title	All Cohorts
Arm/Group Description	Combined for all infants born to women in Second and Third Trimester of pregnancy
Measure Participants	8
Mean (Inter-Quartile Range) [mcg/mL]	2.47

17. Secondary Outcome

Title	Cord Blood Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants
Description	Cord blood concentrations were summarized using using R (version 3.5.1).
Time Frame	at delivery (within 3 days of life for infants).

Outcome Measure Data

Analysis Population Description

All infants with available concentrations born to women on the study

Arm/Group Title	All Cohorts
Arm/Group Description	Combined for all infants born to women in Second and Third Trimester of pregnancy
Measure Participants	5
Mean (Inter-Quartile Range) [mcg/mL]	3.24

18. Secondary Outcome

Title	Plasma Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants
Description	Plasma blood concentrations were summarized using using R (version 3.5.1).
Time Frame	at delivery - (within 3 days of life for infants).

Outcome Measure Data

Analysis Population Description

All infants with available concentrations born to women on the study

Arm/Group Title	All Cohorts
Arm/Group Description	Combined for all infants born to women in Second and Third Trimester of pregnancy
Measure Participants	8
Mean (Inter-Quartile Range) [mcg/mL]	5.31

19. Secondary Outcome

Title	Number of Participants With Discontinuation of Study Drug Due to Intolerance (Tolerability of Study Drug Regimen - i.e., RPT, INH, and Pyridoxine)
Description	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

Outcome Measure Data

Analysis Population Description

All participants enrolled on the study

Arm/Group Title	Cohort 1 (Pregnant Women Enrolled in the Second Trimester)	Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Arm/Group Description	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.	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.
Measure Participants	25	25
Count of Participants [Participants]	0 0%	0 0%

20. Secondary Outcome

Title	Number of Mothers With Active TB up to 24 Weeks Postpartum
Description	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

Outcome Measure Data

Analysis Population Description

All participants enrolled on the study

Arm/Group Title	Cohort 1 (Pregnant Women Enrolled in the Second Trimester)	Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Arm/Group Description	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.	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.
Measure Participants	25	25
Count of Participants [Participants]	0 0%	0 0%

21. Secondary Outcome

Title	Number of Infants With Active TB up to 24 Weeks of Life
Description	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

Outcome Measure Data

Analysis Population Description

All live born infants enrolled on the study

Arm/Group Title	Cohort 1(Infants Born to Women Enrolled in Second Trimester)	Cohort 2 (Infants Born to Women Enrolled in Third Trimester)
Arm/Group Description	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.	Participants will receive 12 directly observed once-weekly doses of RPT, INH, and pyridoxine (vitamin B6) at study entry and at 11 weekly follow-up visits.
Measure Participants	24	25
Count of Participants [Participants]	0 0%	0 0%

22. Secondary Outcome

Title	Clearance (CL/F) of INH
Description	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).

Outcome Measure Data

Analysis Population Description

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/Group Title	All Cohorts
Arm/Group Description	All participants with intensive and sparse PK results at all doses in all stages of pregnancy were used for analysis
Measure Participants	49
CL/F (slow acetylators)	8.98 (47)
CL/F (fast acetylators)	32.7 (10)

23. Secondary Outcome

Title	Absorption (ka) of INH
Description	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).

Outcome Measure Data

Analysis Population Description

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/Group Title	All Cohorts
Arm/Group Description	All participants with intensive and sparse PK results at all doses in all stages of pregnancy were used for analysis
Measure Participants	49
Mean (Standard Error) [hr-1]	1.74 (49)

24. Secondary Outcome

Title	Volume of Distribution of INH
Description	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).

Outcome Measure Data

Analysis Population Description

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/Group Title	All Cohorts
Arm/Group Description	All participants with intensive and sparse PK results at all doses in all stages of pregnancy were used for analysis
Measure Participants	49
Mean (Standard Error) [L]	107 (12)

Adverse Events

Time Frame	Measured from study entry through participants last study visit at 24 weeks after delivery
Adverse Event Reporting Description	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.
Arm/Group Title	Cohort 1 (Pregnant Women Enrolled in Their Second Trimester)		Cohort 2 (Pregnant Women Enrolled in Their Third Trimester)
Arm/Group Description	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.		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.
All Cause Mortality
	Cohort 1 (Pregnant Women Enrolled in Their Second Trimester)		Cohort 2 (Pregnant Women Enrolled in Their Third Trimester)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/25 (4%)		0/25 (0%)
Serious Adverse Events
	Cohort 1 (Pregnant Women Enrolled in Their Second Trimester)		Cohort 2 (Pregnant Women Enrolled in Their Third Trimester)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/25 (8%)		3/25 (12%)
Pregnancy, puerperium and perinatal conditions
Gestational hypertension	0/25 (0%)		2/25 (8%)
Postpartum haemorrhage	0/25 (0%)		1/25 (4%)
Premature separation of placenta	2/25 (8%)		0/25 (0%)
Other (Not Including Serious) Adverse Events
	Cohort 1 (Pregnant Women Enrolled in Their Second Trimester)		Cohort 2 (Pregnant Women Enrolled in Their Third Trimester)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/25 (96%)		25/25 (100%)
Blood and lymphatic system disorders
Iron deficiency anaemia	4/25 (16%)		0/25 (0%)
Cardiac disorders
Palpitations	2/25 (8%)		0/25 (0%)
Eye disorders
Eye pain	2/25 (8%)		1/25 (4%)
Ocular hyperaemia	2/25 (8%)		1/25 (4%)
Gastrointestinal disorders
Abdominal discomfort	0/25 (0%)		2/25 (8%)
Abdominal pain	5/25 (20%)		3/25 (12%)
Abdominal pain lower	3/25 (12%)		3/25 (12%)
Abdominal pain upper	5/25 (20%)		2/25 (8%)
Dyspepsia	3/25 (12%)		0/25 (0%)
Gastritis	2/25 (8%)		1/25 (4%)
Vomiting	3/25 (12%)		0/25 (0%)
General disorders
Chest pain	2/25 (8%)		1/25 (4%)
Malaise	5/25 (20%)		0/25 (0%)
Oedema peripheral	3/25 (12%)		1/25 (4%)
Pyrexia	2/25 (8%)		2/25 (8%)
Infections and infestations
Upper respiratory tract infection	2/25 (8%)		1/25 (4%)
Urinary tract infection	3/25 (12%)		2/25 (8%)
Vulvovaginal candidiasis	2/25 (8%)		3/25 (12%)
Injury, poisoning and procedural complications
Incision site pain	0/25 (0%)		2/25 (8%)
Investigations
Alanine aminotransferase increased	4/25 (16%)		5/25 (20%)
Aspartate aminotransferase increased	6/25 (24%)		7/25 (28%)
Blood albumin decreased	20/25 (80%)		21/25 (84%)
Blood bilirubin increased	2/25 (8%)		0/25 (0%)
Blood pressure increased	5/25 (20%)		3/25 (12%)
Haemoglobin decreased	15/25 (60%)		10/25 (40%)
Platelet count decreased	2/25 (8%)		0/25 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/25 (8%)		0/25 (0%)
Back pain	3/25 (12%)		3/25 (12%)
Muscle spasms	2/25 (8%)		0/25 (0%)
Neck pain	0/25 (0%)		2/25 (8%)
Pain in extremity	4/25 (16%)		2/25 (8%)
Nervous system disorders
Headache	6/25 (24%)		5/25 (20%)
Pregnancy, puerperium and perinatal conditions
Gestational hypertension	2/25 (8%)		0/25 (0%)
Renal and urinary disorders
Dysuria	4/25 (16%)		1/25 (4%)
Reproductive system and breast disorders
Pelvic pain	8/25 (32%)		4/25 (16%)
Vaginal discharge	2/25 (8%)		4/25 (16%)
Vaginal haemorrhage	2/25 (8%)		0/25 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	5/25 (20%)		1/25 (4%)
Dyspnoea	4/25 (16%)		1/25 (4%)
Oropharyngeal pain	1/25 (4%)		2/25 (8%)
Pharyngeal inflammation	2/25 (8%)		0/25 (0%)
Rhinorrhoea	4/25 (16%)		0/25 (0%)
Skin and subcutaneous tissue disorders
Pruritus	2/25 (8%)		0/25 (0%)
Vascular disorders
Hypertension	2/25 (8%)		1/25 (4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

In accordance with the Clinical Trials Agreement between NIAID (DAIDS) and company collaborators, NIAID (DAIDS) provides companies with a copy of any abstract, press release, or manuscript prior to submission for publication with sufficient time for company review and comment. The publication/other disclosure can be delayed for up to 30 additional business days for manuscripts and five (5) business days for abstracts, to preserve U.S. or foreign patent or other intellectual property rights.