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CompletedNCT02651259Updated Nov 4, 2021Results posted

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

A Phase 1/2 interventional study of Rifapentine (RPT) and Isoniazid (INH) in Tuberculosis, sponsored by National Institute of Allergy and Infectious Diseases (NIAID). Completed at 5 sites in 5 countries. Open to female participants aged 18 Years and older, including healthy volunteers. Per ClinicalTrials.gov, last updated 2021-11-04.

Sponsored by National Institute of Allergy and Infectious Diseases (NIAID) · Phase 1/2, Interventional, and Treatment

Phase
Phase 1/2
Study type
Interventional
Enrollment
50
Allocation
Non-randomized
Ages
18 Years and older
Sex
Female
01

Study 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).

Read the 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.

02

Conditions studied

  • Tuberculosis

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03

Who can participate

Ages eligible
18 Years and older
Sexes eligible
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

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)
04

Study design

Phase
Phase 1 / Phase 2
Primary purpose
Treatment
Allocation
Non-randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
50 participants (actual)

Study arms

  • 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) · Drug: Isoniazid (INH) · Dietary Supplement: Pyridoxine (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) · Drug: Isoniazid (INH) · Dietary Supplement: Pyridoxine (vitamin B6)

Interventions

  • DrugRifapentine (RPT)

    900 mg of RPT

    Also known as: Rifamycin

  • DrugIsoniazid (INH)

    900 mg of INH

    Also known as: isonicotinyl hydrazine,

  • Dietary supplementPyridoxine (vitamin B6)

    25 mg to 100 mg of pyridoxine, based on the current local, national, or international dosing guidelines.

    Also known as: Vitamin B6

05

What researchers measure

Primary outcomes

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

    PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Calculated an average CL for all women in the 2nd trimester (cohort I) and all women in the 3rd trimester (cohort II)

    Time frame: Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).

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

    PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption and a separate compartment for metabolite formation * Estimated a single des-RPT CLmet/F for the whole population Note: that the mean stated below is actually the value that is obtained from a population analysis and represents a population estimate with the relative standard error

    Time frame: Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).

  3. Absorption Rate Constant (ka) for Rifapentine (RPT)

    PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Estimated the transit compartment rate constant (ktr), which is synonymous with the absorption constant (ka), for the whole population Note that the mean stated below is actually the value that is obtained from a population analysis and represents a population estimate

    Time frame: Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).

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

    PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Estimated a single RPT Vc/F for for the whole population Note: that the mean stated below is actually the value that is obtained from a population analysis and represents a population estimate with the relative standard error

    Time frame: Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).

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

    At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used.

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

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

    At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) and were used.

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

  7. Percentage of Participants With All Grade 3 and 4 AEs

    At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used.

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

  8. Percentage of Participants With All Serious AEs

    At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used.

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

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

    At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used.

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

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

    At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used.

    Time frame: Measured from birth through infants' last study visit at 24 weeks after birth

Secondary outcomes

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

    PK parameters from postpartum women were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Calculated an average CL for all post-partum individuals

    Time frame: Data used in the population PK analysis for postpartum women included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).

  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

    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).

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

    PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Obtained Cmax by model-based estimation

    Time frame: Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).

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

    PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Obtained Cmin by model-based estimation

    Time frame: Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).

  5. Cord Blood Concentrations of Rifapentine (RPT) Among Infants

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

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

  6. Plasma Concentrations of Rifapentine (RPT) Among Infants

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

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

  7. Cord Blood Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants

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

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

  8. Plasma Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants

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

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

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

    At entry and follow-up, all lab results, sign and symptoms, and diagnoses will be recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that result in discontinuation of study drug regimen, and that meet criteria for EAE reporting will be further evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used.

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

  10. Number of Mothers With Active TB up to 24 Weeks Postpartum

    Based on site-specified confirmatory TB test. If women and infants were diagnosed with active TB during study they would be referred to local care for TB management and treatment.

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

  11. Number of Infants With Active TB up to 24 Weeks of Life

    Based on site-specified confirmatory TB test. If women and infants were diagnosed with active TB during study they would be referred to local care for TB management and treatment.

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

  12. Clearance (CL/F) of INH

    PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with 2 mixtures to characterize subpopulations based on acetylation status * Estimated a separate INH CL/F based on acetylation status (fast, slow)

    Time frame: Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).

  13. Absorption (ka) of INH

    PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). • Estimated a single absorption rate constant (ka) for the whole population

    Time frame: Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).

  14. Volume of Distribution of INH

    PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). • Estimated a single INH Vc/F for the whole population

    Time frame: Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).

06

Results

Posted May 6, 2020

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 flow — Overall Study
MilestoneCohort 1 (Pregnant Women Enrolled in the Second Trimester)Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Started2525
Completed2525
Not completed00

Outcome measures

PrimaryClearance Relative to Bioavailability (CL/F) for Rifapentine (RPT) for Intensive and Sparse PK

PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Calculated an average CL for all women in the 2nd trimester (cohort I) and all women in the 3rd trimester (cohort II)

Time frame:
Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).
Reported as:
Mean · L/hr
Clearance Relative to Bioavailability (CL/F) for Rifapentine (RPT) for Intensive and Sparse PK
L/hrCohort 1 (Pregnant Women Enrolled in the Second Trimester)Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Clearance Relative to Bioavailability (CL/F) for Rifapentine (RPT) for Intensive and Sparse PK1.4 (1.26 to 1.60)1.50 (1.25 to 1.66)
PrimaryClearance Relative to Bioavailability (CLmet/F) for Desacetyl Rifapentine (Des-RPT)

PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption and a separate compartment for metabolite formation * Estimated a single des-RPT CLmet/F for the whole population Note: that the mean stated below is actually the value that is obtained from a population analysis and represents a population estimate with the relative standard error

Time frame:
Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).
Reported as:
Mean · L/hr
Clearance Relative to Bioavailability (CLmet/F) for Desacetyl Rifapentine (Des-RPT)
L/hrAll Cohorts
Clearance Relative to Bioavailability (CLmet/F) for Desacetyl Rifapentine (Des-RPT)2.82 ± 7
PrimaryAbsorption Rate Constant (ka) for Rifapentine (RPT)

PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Estimated the transit compartment rate constant (ktr), which is synonymous with the absorption constant (ka), for the whole population Note that the mean stated below is actually the value that is obtained from a population analysis and represents a population estimate

Time frame:
Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).
Reported as:
Mean · hr-1
Absorption Rate Constant (ka) for Rifapentine (RPT)
hr-1All Cohorts
Absorption Rate Constant (ka) for Rifapentine (RPT)1.43 ± NA
PrimaryVolume of Distribution Relative to Bioavailability (Vc/F) for Rifapentine (RPT)

PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Estimated a single RPT Vc/F for for the whole population Note: that the mean stated below is actually the value that is obtained from a population analysis and represents a population estimate with the relative standard error

Time frame:
Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).
Reported as:
Mean · L
Volume of Distribution Relative to Bioavailability (Vc/F) for Rifapentine (RPT)
LAll Cohorts
Volume of Distribution Relative to Bioavailability (Vc/F) for Rifapentine (RPT)30.1 ± 5
PrimaryIncidence of Related Serious Adverse Events (SAEs) in Pregnant and Postpartum Women Taking Once-weekly RPT + INH

At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used.

Time frame:
Measured from entry through participants' last study visit at 24 weeks after delivery
Reported as:
Count of participants · Participants
Incidence of Related Serious Adverse Events (SAEs) in Pregnant and Postpartum Women Taking Once-weekly RPT + INH
ParticipantsCohort 1 (Pregnant Women Enrolled in the Second Trimester)Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Incidence of Related Serious Adverse Events (SAEs) in Pregnant and Postpartum Women Taking Once-weekly RPT + INH00
PrimaryPercentage of Participants With Grade 2 Adverse Events (AEs) Judged to be Related to Study Drug Regimen

At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) and were used.

Time frame:
Measured from study entry through participants' last study visit at 24 weeks after delivery
Reported as:
Number · percent of participants
Percentage of Participants With Grade 2 Adverse Events (AEs) Judged to be Related to Study Drug Regimen
percent of participantsCohort 1 (Pregnant Women Enrolled in the Second Trimester)Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Percentage of Participants With Grade 2 Adverse Events (AEs) Judged to be Related to Study Drug Regimen4 (0.1 to 20)0 (0 to 14)
PrimaryPercentage of Participants With All Grade 3 and 4 AEs

At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used.

Time frame:
Measured from study entry through participants' last study visit at 24 weeks after delivery
Reported as:
Number · percent of participants
Percentage of Participants With All Grade 3 and 4 AEs
percent of participantsCohort 1 (Pregnant Women Enrolled in the Second Trimester)Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Percentage of Participants With All Grade 3 and 4 AEs20 (7 to 41)16 (5 to 36)
PrimaryPercentage of Participants With All Serious AEs

At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used.

Time frame:
Measured from study entry through participants' last study visit at 24 weeks after delivery
Reported as:
Number · percent of participants
Percentage of Participants With All Serious AEs
percent of participantsCohort 1 (Pregnant Women Enrolled in the Second Trimester)Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Percentage of Participants With All Serious AEs8 (1 to 26)12 (3 to 31)
PrimaryPercentage of Participants With All AEs Leading to Permanent Discontinuation of Study Drug Regimen (i.e., RPT, INH, and Pyridoxine)

At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used.

Time frame:
Measured from study entry through participants' last study treatment dispensation (approximately for 12 weeks)
Reported as:
Number · percent of participants
Percentage of Participants With All AEs Leading to Permanent Discontinuation of Study Drug Regimen (i.e., RPT, INH, and Pyridoxine)
percent of participantsCohort 1 (Pregnant Women Enrolled in the Second Trimester)Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Percentage of Participants With All AEs Leading to Permanent Discontinuation of Study Drug Regimen (i.e., RPT, INH, and Pyridoxine)0 (0 to 14)0 (0 to 14)
PrimaryPercentage of Participants With Related Serious Adverse Events (AEs) in Infants Born to Women Taking Once-weekly RPT + INH

At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used.

Time frame:
Measured from birth through infants' last study visit at 24 weeks after birth
Reported as:
Number · percent of participants
Percentage of Participants With Related Serious Adverse Events (AEs) in Infants Born to Women Taking Once-weekly RPT + INH
percent of participantsCohort 1 (Infants Born to Women Enrolled in Second Trimester)Cohort 2 (Infants Born to Women Enrolled in Third Trimester)
Percentage of Participants With Related Serious Adverse Events (AEs) in Infants Born to Women Taking Once-weekly RPT + INH0 (0 to 14)0 (0 to 14)
SecondaryClearance Relative to Bioavailability (CL/F) for Rifapentine (RPT)

PK parameters from postpartum women were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Calculated an average CL for all post-partum individuals

Time frame:
Data used in the population PK analysis for postpartum women included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).
Reported as:
Mean · L/hr
Clearance Relative to Bioavailability (CL/F) for Rifapentine (RPT)
L/hrAll Cohorts
Clearance Relative to Bioavailability (CL/F) for Rifapentine (RPT)1.64 (1.6 to 1.68)
SecondaryArea Under the Curve From 0 to 24 Hours (AUC0-24) for RPT and Area Under the Curve From 0 to 24 Hours (AUC0-24) for Des-RPT Pregnant Women in 2nd and 3rd Trimester

PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Obtained AUC by model-based integration

Time frame:
Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).
Reported as:
Mean · hour*mg/L
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
hour*mg/LCohort 1 (Pregnant Women Enrolled in the Second Trimester)Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
AUC (0-24) for RPT424.7 (341.7 to 514.1)406.8 (334.8 to 471.7)
AUC (0-24) for des-RPT158.7 (118.9 to 184.3)153.7 (123.1 to 186.4)
SecondaryMaximum Concentration (Cmax) for RPT Maximum Concentration (Cmax) for Des-RPT Pregnant Women in 2nd and 3rd Trimester

PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Obtained Cmax by model-based estimation

Time frame:
Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).
Reported as:
Mean · mg/L
Maximum Concentration (Cmax) for RPT Maximum Concentration (Cmax) for Des-RPT Pregnant Women in 2nd and 3rd Trimester
mg/LCohort 1 (Pregnant Women Enrolled in the Second Trimester)Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Cmax for RPT30.2 (25.1 to 36.1)28.6 (24.7 to 32.1)
Cmax for des-RPT8.76 (5.91 to 10.8)8.50 (6.82 to 10.0)
SecondaryMaximum Concentration (Cmin) for RPT and Maximum Concentration (Cmin) for Des-RPT Pregnant Women in 2nd and 3rd Trimester

PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Obtained Cmin by model-based estimation

Time frame:
Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).
Reported as:
Mean · mg/L
Maximum Concentration (Cmin) for RPT and Maximum Concentration (Cmin) for Des-RPT Pregnant Women in 2nd and 3rd Trimester
mg/LCohort 1 (Pregnant Women Enrolled in the Second Trimester)Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Cmin for RPT1.45 (0.84 to 1.98)1.58 (0.66 to 2.29)
Cmin for des-RPT1.06 (0.63 to 1.25)1.20 (0.79 to 1.74)
SecondaryCord Blood Concentrations of Rifapentine (RPT) Among Infants

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

Time frame:
at delivery - (within 3 days of life for infants)
Reported as:
Mean · mcg/mL
Cord Blood Concentrations of Rifapentine (RPT) Among Infants
mcg/mLAll Cohorts
Cord Blood Concentrations of Rifapentine (RPT) Among Infants2.97 (1.94 to 4.26)
SecondaryPlasma Concentrations of Rifapentine (RPT) Among Infants

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

Time frame:
at delivery - (within 3 days of life for infants).
Reported as:
Mean · mcg/mL
Plasma Concentrations of Rifapentine (RPT) Among Infants
mcg/mLAll Cohorts
Plasma Concentrations of Rifapentine (RPT) Among Infants2.47 (1.49 to 3.30)
SecondaryCord Blood Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants

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

Time frame:
at delivery (within 3 days of life for infants).
Reported as:
Mean · mcg/mL
Cord Blood Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants
mcg/mLAll Cohorts
Cord Blood Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants3.24 (1.03 to 5.17)
SecondaryPlasma Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants

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

Time frame:
at delivery - (within 3 days of life for infants).
Reported as:
Mean · mcg/mL
Plasma Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants
mcg/mLAll Cohorts
Plasma Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants5.31 (3.73 to 7.37)
SecondaryNumber of Participants With Discontinuation of Study Drug Due to Intolerance (Tolerability of Study Drug Regimen - i.e., RPT, INH, and Pyridoxine)

At entry and follow-up, all lab results, sign and symptoms, and diagnoses will be recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that result in discontinuation of study drug regimen, and that meet criteria for EAE reporting will be further evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used.

Time frame:
Measured from study entry through participants' last study visit at 24 weeks after delivery
Reported as:
Count of participants · Participants
Number of Participants With Discontinuation of Study Drug Due to Intolerance (Tolerability of Study Drug Regimen - i.e., RPT, INH, and Pyridoxine)
ParticipantsCohort 1 (Pregnant Women Enrolled in the Second Trimester)Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Number of Participants With Discontinuation of Study Drug Due to Intolerance (Tolerability of Study Drug Regimen - i.e., RPT, INH, and Pyridoxine)00
SecondaryNumber of Mothers With Active TB up to 24 Weeks Postpartum

Based on site-specified confirmatory TB test. If women and infants were diagnosed with active TB during study they would be referred to local care for TB management and treatment.

Time frame:
Measured from study entry through participants' last study visit at 24 weeks after delivery
Reported as:
Count of participants · Participants
Number of Mothers With Active TB up to 24 Weeks Postpartum
ParticipantsCohort 1 (Pregnant Women Enrolled in the Second Trimester)Cohort 2 (Pregnant Women Enrolled in the Third Trimester)
Number of Mothers With Active TB up to 24 Weeks Postpartum00
SecondaryNumber of Infants With Active TB up to 24 Weeks of Life

Based on site-specified confirmatory TB test. If women and infants were diagnosed with active TB during study they would be referred to local care for TB management and treatment.

Time frame:
Measured from birth through participants' last study visit at 24 weeks after delivery
Reported as:
Count of participants · Participants
Number of Infants With Active TB up to 24 Weeks of Life
ParticipantsCohort 1(Infants Born to Women Enrolled in Second Trimester)Cohort 2 (Infants Born to Women Enrolled in Third Trimester)
Number of Infants With Active TB up to 24 Weeks of Life00
SecondaryClearance (CL/F) of INH

PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with 2 mixtures to characterize subpopulations based on acetylation status * Estimated a separate INH CL/F based on acetylation status (fast, slow)

Time frame:
Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).
Reported as:
Mean · L/hr
Clearance (CL/F) of INH
L/hrAll Cohorts
CL/F (slow acetylators)8.98 ± 47
CL/F (fast acetylators)32.7 ± 10
SecondaryAbsorption (ka) of INH

PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). • Estimated a single absorption rate constant (ka) for the whole population

Time frame:
Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).
Reported as:
Mean · hr-1
Absorption (ka) of INH
hr-1All Cohorts
Absorption (ka) of INH1.74 ± 49
SecondaryVolume of Distribution of INH

PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). • Estimated a single INH Vc/F for the whole population

Time frame:
Data used in the population PK analysis included the intensive PK visit (pre-dose (t0) and 0.5, 1, 2. 4, 5, 8, 12, 24, 48, 72 hours post-dose) and sparse PK visit (1, 4, 24, 48 hours post-dose).
Reported as:
Mean · L
Volume of Distribution of INH
LAll Cohorts
Volume of Distribution of INH107 ± 12

Adverse events

Collected over Measured from study entry through participants last study visit at 24 weeks after delivery. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Cohort 1 (Pregnant Women Enrolled in Their Second Trimester)1/25 (4%)2/25 (8%)24/25 (96%)
Cohort 2 (Pregnant Women Enrolled in Their Third Trimester)0/25 (0%)3/25 (12%)25/25 (100%)
Most frequent serious events
Most frequent serious events
EventCohort 1 (Pregnant Women Enrolled in Their Second Trimester)Cohort 2 (Pregnant Women Enrolled in Their Third Trimester)
Gestational hypertensionPregnancy, puerperium and perinatal conditions0/252/25
Premature separation of placentaPregnancy, puerperium and perinatal conditions2/250/25
Postpartum haemorrhagePregnancy, puerperium and perinatal conditions0/251/25
Most frequent other events
Showing 10 of 44
Most frequent other events
EventCohort 1 (Pregnant Women Enrolled in Their Second Trimester)Cohort 2 (Pregnant Women Enrolled in Their Third Trimester)
Blood albumin decreasedInvestigations20/2521/25
Haemoglobin decreasedInvestigations15/2510/25
Pelvic painReproductive system and breast disorders8/254/25
Aspartate aminotransferase increasedInvestigations6/257/25
HeadacheNervous system disorders6/255/25
Abdominal painGastrointestinal disorders5/253/25
Abdominal pain upperGastrointestinal disorders5/252/25
MalaiseGeneral disorders5/250/25
Alanine aminotransferase increasedInvestigations4/255/25
Blood pressure increasedInvestigations5/253/25

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)Cohort 1 (Pregnant Women Enrolled in the Second Trimester)Cohort 2 (Pregnant Women Enrolled in the Third Trimester)Total
<=18 years134
Between 18 and 65 years242246
>=65 years000
Age, Continuous
Age, Continuous(years)Cohort 1 (Pregnant Women Enrolled in the Second Trimester)Cohort 2 (Pregnant Women Enrolled in the Third Trimester)Total
Median26 (22 to 33)27 (20 to 31)27 (20 to 32)
Sex: Female, Male
Sex: Female, Male(Participants)Cohort 1 (Pregnant Women Enrolled in the Second Trimester)Cohort 2 (Pregnant Women Enrolled in the Third Trimester)Total
Female252550
Male000
Race/Ethnicity, Customized
Race/Ethnicity, Customized(Participants)Cohort 1 (Pregnant Women Enrolled in the Second Trimester)Cohort 2 (Pregnant Women Enrolled in the Third Trimester)Total
Black Non-Hispanic242347
Asian, Pacific Islander123
Region of Enrollment
Region of Enrollment(participants)Cohort 1 (Pregnant Women Enrolled in the Second Trimester)Cohort 2 (Pregnant Women Enrolled in the Third Trimester)Total
Haiti11516
Malawi213
Zimbabwe91221
Kenya257
Thailand123
HIV-1 status
HIV-1 status(Participants)Cohort 1 (Pregnant Women Enrolled in the Second Trimester)Cohort 2 (Pregnant Women Enrolled in the Third Trimester)Total
HIV-1 uninfected151530
HIV-1 infected101020
Absolute CD4 count
Absolute CD4 count(cells/mm^3)Cohort 1 (Pregnant Women Enrolled in the Second Trimester)Cohort 2 (Pregnant Women Enrolled in the Third Trimester)Total
Median586 (415 to 846)489 (368 to 952)510 (390 to 877)
World Health Organization (WHO) clinical stage
World Health Organization (WHO) clinical stage(Participants)Cohort 1 (Pregnant Women Enrolled in the Second Trimester)Cohort 2 (Pregnant Women Enrolled in the Third Trimester)Total
Clinical Stage 1101020
Clinical Stage 2000
Clinical Stage 3000
Clinical Stage 4000

6 further baseline measures are reported on the registry.

07

Study locations

5 sites
  • Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS
    Port-au-Prince, HT-6110, Haiti
  • Kenya Medical Research Institute / Walter Reed Project Clinical Research Center, Kericho CRS
    Kericho, 20200, Kenya
  • Malawi CRS
    Lilongwe, Central Malawi, Malawi
  • Siriraj Hospital ,Mahidol University NICHD CRS
    Bangkok, Bangkoknoi 10700, Thailand
  • Harare Family Care CRS
    Harare, Zimbabwe
08

References and documents

Publications

  • Mathad JS, Savic R, Britto P, Jayachandran P, Wiesner L, Montepiedra G, Norman J, Zhang N, Townley E, Chakhtoura N, Bradford S, Patil S, Popson S, Chipato T, Rouzier V, Langat D, Chalermchockcharoentkit A, Kamthunzi P, Gupta A, Dooley KE. Pharmacokinetics and Safety of 3 Months of Weekly Rifapentine and Isoniazid for Tuberculosis Prevention in Pregnant Women. Clin Infect Dis. 2022 May 3;74(9):1604-1613. doi: 10.1093/cid/ciab665. PubMed 34323955 ↗

Study documents

  • Study protocol · Nov 10, 2015
  • Statistical analysis plan · Jun 26, 2019
  • Statistical analysis plan · Mar 31, 2020

Documents are hosted by the registry — open the source record to download them.

09

Registry details

Key details

Study ID
NCT02651259
Lead sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Responsible party
Sponsor
First posted
Jan 8, 2016
Start date
Mar 13, 2017
Primary completion
Apr 10, 2019
Completion
Apr 10, 2019
Results posted
May 6, 2020
Last update
Nov 4, 2021

Study contacts

Jyoti S. Mathad, MD, MSc
study chair · Weill Medical College of Cornell University

Oversight

Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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