Trial Outcomes & Findings for Evaluating PK, Tolerability, and Safety of Rifapentine and Isoniazid in Pregnant and Postpartum Women (NCT NCT02651259)

Last Updated: 2021-11-04

Results Overview

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)

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

50 participants

Primary outcome timeframe

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).

Results posted on

2021-11-04

Participant Flow

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).

Participant milestones

Participant milestones
Measure	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.	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.
Overall Study STARTED	25	25
Overall Study COMPLETED	25	25
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

CD4 cell counts were assessed for HIV-1 infected mothers only

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=25 Participants 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.	Cohort 2 (Pregnant Women Enrolled in the Third Trimester) n=25 Participants 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 n=50 Participants Total of all reporting groups
Age, Categorical <=18 years	1 Participants n=25 Participants	3 Participants n=25 Participants	4 Participants n=50 Participants
Age, Categorical Between 18 and 65 years	24 Participants n=25 Participants	22 Participants n=25 Participants	46 Participants n=50 Participants
Age, Categorical >=65 years	0 Participants n=25 Participants	0 Participants n=25 Participants	0 Participants n=50 Participants
Age, Continuous	26 years n=25 Participants	27 years n=25 Participants	27 years n=50 Participants
Sex: Female, Male Female	25 Participants n=25 Participants	25 Participants n=25 Participants	50 Participants n=50 Participants
Sex: Female, Male Male	0 Participants n=25 Participants	0 Participants n=25 Participants	0 Participants n=50 Participants
Race/Ethnicity, Customized Black Non-Hispanic	24 Participants n=25 Participants	23 Participants n=25 Participants	47 Participants n=50 Participants
Race/Ethnicity, Customized Asian, Pacific Islander	1 Participants n=25 Participants	2 Participants n=25 Participants	3 Participants n=50 Participants
Region of Enrollment Haiti	11 participants n=25 Participants	5 participants n=25 Participants	16 participants n=50 Participants
Region of Enrollment Malawi	2 participants n=25 Participants	1 participants n=25 Participants	3 participants n=50 Participants
Region of Enrollment Zimbabwe	9 participants n=25 Participants	12 participants n=25 Participants	21 participants n=50 Participants
Region of Enrollment Kenya	2 participants n=25 Participants	5 participants n=25 Participants	7 participants n=50 Participants
Region of Enrollment Thailand	1 participants n=25 Participants	2 participants n=25 Participants	3 participants n=50 Participants
HIV-1 status HIV-1 uninfected	15 Participants n=25 Participants	15 Participants n=25 Participants	30 Participants n=50 Participants
HIV-1 status HIV-1 infected	10 Participants n=25 Participants	10 Participants n=25 Participants	20 Participants n=50 Participants
Absolute CD4 count	586 cells/mm^3 n=10 Participants • CD4 cell counts were assessed for HIV-1 infected mothers only	489 cells/mm^3 n=10 Participants • CD4 cell counts were assessed for HIV-1 infected mothers only	510 cells/mm^3 n=20 Participants • CD4 cell counts were assessed for HIV-1 infected mothers only
World Health Organization (WHO) clinical stage Clinical Stage 1	10 Participants n=10 Participants • WHO stages were assessed for HIV-1 infected mothers only	10 Participants n=10 Participants • WHO stages were assessed for HIV-1 infected mothers only	20 Participants n=20 Participants • WHO stages were assessed for HIV-1 infected mothers only
World Health Organization (WHO) clinical stage Clinical Stage 2	0 Participants n=10 Participants • WHO stages were assessed for HIV-1 infected mothers only	0 Participants n=10 Participants • WHO stages were assessed for HIV-1 infected mothers only	0 Participants n=20 Participants • WHO stages were assessed for HIV-1 infected mothers only
World Health Organization (WHO) clinical stage Clinical Stage 3	0 Participants n=10 Participants • WHO stages were assessed for HIV-1 infected mothers only	0 Participants n=10 Participants • WHO stages were assessed for HIV-1 infected mothers only	0 Participants n=20 Participants • WHO stages were assessed for HIV-1 infected mothers only
World Health Organization (WHO) clinical stage Clinical Stage 4	0 Participants n=10 Participants • WHO stages were assessed for HIV-1 infected mothers only	0 Participants n=10 Participants • WHO stages were assessed for HIV-1 infected mothers only	0 Participants n=20 Participants • WHO stages were assessed for HIV-1 infected mothers only
Weight	59 kilograms n=25 Participants	61 kilograms n=25 Participants	61 kilograms n=50 Participants
Gestational Age at Screening	20 weeks n=25 Participants	30 weeks n=25 Participants	26 weeks n=50 Participants
Mid-upper arm circumference (MUAC)	27 centimeters n=25 Participants	27 centimeters n=25 Participants	27 centimeters n=50 Participants
Serum glutamic-oxaloacetic transaminase (SGOT)	21 units/L n=25 Participants	21 units/L n=25 Participants	21 units/L n=50 Participants
Serum glutamic pyruvic transaminase (SGPT)	17 units/L n=25 Participants	14 units/L n=25 Participants	15 units/L n=50 Participants
Prothrombin Time result	10 seconds n=25 Participants	11 seconds n=25 Participants	10 seconds n=50 Participants

PRIMARY outcome

Timeframe: 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.

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)

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=24 Participants 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.	Cohort 2 (Pregnant Women Enrolled in the Third Trimester) n=25 Participants 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.
Clearance Relative to Bioavailability (CL/F) for Rifapentine (RPT) for Intensive and Sparse PK	1.4 L/hr Interval 1.26 to 1.6	1.50 L/hr Interval 1.25 to 1.66

PRIMARY outcome

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=49 Participants 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.	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.
Clearance Relative to Bioavailability (CLmet/F) for Desacetyl Rifapentine (Des-RPT)	2.82 L/hr Standard Error 7	—

PRIMARY outcome

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=49 Participants 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.	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.
Absorption Rate Constant (ka) for Rifapentine (RPT)	1.43 hr-1 Standard Error NA The absorption rate is calculated from another estimated parameter and hence there is no Relative Standard Error to report and hence the value of N/A was entered.	—

PRIMARY outcome

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

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

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=49 Participants 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.	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.
Volume of Distribution Relative to Bioavailability (Vc/F) for Rifapentine (RPT)	30.1 L Standard Error 5	—

PRIMARY outcome

Timeframe: Measured from entry through participants' last study visit at 24 weeks after delivery

Population: All participants enrolled in the study

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.

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=25 Participants 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.	Cohort 2 (Pregnant Women Enrolled in the Third Trimester) n=25 Participants 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.
Incidence of Related Serious Adverse Events (SAEs) in Pregnant and Postpartum Women Taking Once-weekly RPT + INH	0 Participants	0 Participants

PRIMARY outcome

Timeframe: Measured from study entry through participants' last study visit at 24 weeks after delivery

Population: All participant enrolled on the study

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=25 Participants 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.	Cohort 2 (Pregnant Women Enrolled in the Third Trimester) n=25 Participants 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.
Percentage of Participants With Grade 2 Adverse Events (AEs) Judged to be Related to Study Drug Regimen	4 percent of participants Interval 0.1 to 20.0	0 percent of participants Interval 0.0 to 14.0

PRIMARY outcome

Timeframe: Measured from study entry through participants' last study visit at 24 weeks after delivery

Population: All participants enrolled on the study

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=25 Participants 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.	Cohort 2 (Pregnant Women Enrolled in the Third Trimester) n=25 Participants 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.
Percentage of Participants With All Grade 3 and 4 AEs	20 percent of participants Interval 7.0 to 41.0	16 percent of participants Interval 5.0 to 36.0

PRIMARY outcome

Timeframe: Measured from study entry through participants' last study visit at 24 weeks after delivery

Population: All participants enrolled on the study

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=25 Participants 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.	Cohort 2 (Pregnant Women Enrolled in the Third Trimester) n=25 Participants 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.
Percentage of Participants With All Serious AEs	8 percent of participants Interval 1.0 to 26.0	12 percent of participants Interval 3.0 to 31.0

PRIMARY outcome

Timeframe: Measured from study entry through participants' last study treatment dispensation (approximately for 12 weeks)

Population: All participants enrolled on the study

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=25 Participants 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.	Cohort 2 (Pregnant Women Enrolled in the Third Trimester) n=25 Participants 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.
Percentage of Participants With All AEs Leading to Permanent Discontinuation of Study Drug Regimen (i.e., RPT, INH, and Pyridoxine)	0 percent of participants Interval 0.0 to 14.0	0 percent of participants Interval 0.0 to 14.0

PRIMARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=24 Participants 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.	Cohort 2 (Pregnant Women Enrolled in the Third Trimester) n=25 Participants 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.
Percentage of Participants With Related Serious Adverse Events (AEs) in Infants Born to Women Taking Once-weekly RPT + INH	0 percent of participants Interval 0.0 to 14.0	0 percent of participants Interval 0.0 to 14.0

SECONDARY outcome

Timeframe: 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.

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

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=22 Participants 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.	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.
Clearance Relative to Bioavailability (CL/F) for Rifapentine (RPT)	1.64 L/hr Interval 1.6 to 1.68	—

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=22 Participants 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.	Cohort 2 (Pregnant Women Enrolled in the Third Trimester) n=19 Participants 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.
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 Interval 341.7 to 514.1	406.8 hour*mg/L Interval 334.8 to 471.7
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 Interval 118.9 to 184.3	153.7 hour*mg/L Interval 123.1 to 186.4

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=22 Participants 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.	Cohort 2 (Pregnant Women Enrolled in the Third Trimester) n=19 Participants 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.
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 Interval 25.1 to 36.1	28.6 mg/L Interval 24.7 to 32.1
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 Interval 5.91 to 10.8	8.50 mg/L Interval 6.82 to 10.0

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=23 Participants 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.	Cohort 2 (Pregnant Women Enrolled in the Third Trimester) n=25 Participants 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.
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 Interval 0.63 to 1.25	1.20 mg/L Interval 0.79 to 1.74
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 Interval 0.84 to 1.98	1.58 mg/L Interval 0.66 to 2.29

SECONDARY outcome

Timeframe: at delivery - (within 3 days of life for infants)

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

Cord blood concentrations were summarized using using R (version 3.5.1).

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=5 Participants 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.	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.
Cord Blood Concentrations of Rifapentine (RPT) Among Infants	2.97 mcg/mL Interval 1.94 to 4.26	—

SECONDARY outcome

Timeframe: at delivery - (within 3 days of life for infants).

Population: All infants with available concentrations born to women on the study

Plasma concentrations were summarized using using R (version 3.5.1).

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=8 Participants 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.	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.
Plasma Concentrations of Rifapentine (RPT) Among Infants	2.47 mcg/mL Interval 1.49 to 3.3	—

SECONDARY outcome

Timeframe: at delivery (within 3 days of life for infants).

Population: All infants with available concentrations born to women on the study

Cord blood concentrations were summarized using using R (version 3.5.1).

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=5 Participants 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.	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.
Cord Blood Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants	3.24 mcg/mL Interval 1.03 to 5.17	—

SECONDARY outcome

Timeframe: at delivery - (within 3 days of life for infants).

Population: All infants with available concentrations born to women on the study

Plasma blood concentrations were summarized using using R (version 3.5.1).

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=8 Participants 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.	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.
Plasma Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants	5.31 mcg/mL Interval 3.73 to 7.37	—

SECONDARY outcome

Timeframe: Measured from study entry through participants' last study visit at 24 weeks after delivery

Population: All participants enrolled on the study

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.

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=25 Participants 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.	Cohort 2 (Pregnant Women Enrolled in the Third Trimester) n=25 Participants 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.
Number of Participants With Discontinuation of Study Drug Due to Intolerance (Tolerability of Study Drug Regimen - i.e., RPT, INH, and Pyridoxine)	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Measured from study entry through participants' last study visit at 24 weeks after delivery

Population: All participants enrolled on the study

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.

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=25 Participants 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.	Cohort 2 (Pregnant Women Enrolled in the Third Trimester) n=25 Participants 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.
Number of Mothers With Active TB up to 24 Weeks Postpartum	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Measured from birth through participants' last study visit at 24 weeks after delivery

Population: All live born infants enrolled on the study

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.

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=24 Participants 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.	Cohort 2 (Pregnant Women Enrolled in the Third Trimester) n=25 Participants 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.
Number of Infants With Active TB up to 24 Weeks of Life	0 Participants	0 Participants

SECONDARY outcome

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

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)

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=49 Participants 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.	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.
Clearance (CL/F) of INH CL/F (slow acetylators)	8.98 L/hr Standard Error 47	—
Clearance (CL/F) of INH CL/F (fast acetylators)	32.7 L/hr Standard Error 10	—

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=49 Participants 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.	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.
Absorption (ka) of INH	1.74 hr-1 Standard Error 49	—

SECONDARY outcome

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

Outcome measures

Outcome measures
Measure	Cohort 1 (Pregnant Women Enrolled in the Second Trimester) n=49 Participants 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.	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.
Volume of Distribution of INH	107 L Standard Error 12	—

Adverse Events

Cohort 1 (Pregnant Women Enrolled in Their Second Trimester)

Serious events: 2 serious events

Other events: 24 other events

Deaths: 1 deaths

Cohort 2 (Pregnant Women Enrolled in Their Third Trimester)

Serious events: 3 serious events

Other events: 25 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Cohort 1 (Pregnant Women Enrolled in Their Second Trimester) n=25 participants at risk 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.	Cohort 2 (Pregnant Women Enrolled in Their Third Trimester) n=25 participants at risk 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.
Pregnancy, puerperium and perinatal conditions Gestational hypertension	0.00% 0/25 • 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.	8.0% 2/25 • 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.
Pregnancy, puerperium and perinatal conditions Postpartum haemorrhage	0.00% 0/25 • 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.	4.0% 1/25 • 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.
Pregnancy, puerperium and perinatal conditions Premature separation of placenta	8.0% 2/25 • 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.	0.00% 0/25 • 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.

Other adverse events

Additional Information

Melissa Allen, Director, IMPAACT Operations Center

Family Health International (FHI 360

Phone: (919) 405-1429

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER