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
Overview
- Phase
- Phase 1
- Intervention
- Pyridoxine (vitamin B6)
- Conditions
- Tuberculosis
- Sponsor
- National Institute of Allergy and Infectious Diseases (NIAID)
- Enrollment
- 50
- Locations
- 5
- Primary Endpoint
- Clearance Relative to Bioavailability (CL/F) for Rifapentine (RPT) for Intensive and Sparse PK
- Status
- Completed
- Last Updated
- 4 years ago
Overview
Brief Summary
The purpose of this study was to evaluate the pharmacokinetics (PK), tolerability, and safety of once-weekly doses of rifapentine (RPT) and isoniazid (INH) in HIV-1-infected and HIV-1-uninfected pregnant and postpartum women with latent tuberculosis (TB).
Detailed Description
TB is a major cause of illness and death in women of reproductive age. Pregnant and postpartum women with latent TB are at higher risk of developing active TB. This study evaluated the pharmacokinetics, tolerability, and safety of 12 once-weekly doses of RPT and INH in HIV-1-infected and HIV-1-uninfected pregnant and postpartum women with latent TB. This study enrolled HIV-1-infected and HIV-1-uninfected pregnant women with latent TB and their infants into two cohorts based on gestation. Cohort 1 participants were enrolled in their second trimester (greater than or equal to 14 to less than 28 weeks), and Cohort 2 participants were enrolled in their third trimester (greater than or equal to 28 to less than or equal to 34 weeks). All participants received 12 directly observed once-weekly doses of RPT, INH, and pyridoxine (vitamin B6) at study entry and at 11 weekly follow-up visits. Study researchers would perform an interim analysis to assess the PK of RPT during the study, and a dose adjustment could have been recommended based on this analysis. Study visits occurred at days 0-3, once a week through week 11, and once a month until 24 weeks after delivery. Visits would include physical examinations, obstetrical exams, and blood collection. Infants were followed monthly until 24 weeks after birth.
Investigators
Eligibility Criteria
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
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
Arms & Interventions
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.
Intervention: Pyridoxine (vitamin B6)
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.
Intervention: Rifapentine (RPT)
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.
Intervention: Isoniazid (INH)
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.
Intervention: Pyridoxine (vitamin B6)
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.
Intervention: Rifapentine (RPT)
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.
Intervention: Isoniazid (INH)
Outcomes
Primary Outcomes
Clearance Relative to Bioavailability (CL/F) for Rifapentine (RPT) for Intensive and Sparse PK
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).
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)
Absorption Rate Constant (ka) for Rifapentine (RPT)
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).
PK parameters were determined from plasma concentration-time profiles using a nonlinear mixed effects model (version 7.4; ICON PLC, Dublin, Ireland). * Developed a 1 compartment PK model with transit compartments for oral absorption * Estimated the transit compartment rate constant (ktr), which is synonymous with the absorption constant (ka), for the whole population Note that the mean stated below is actually the value that is obtained from a population analysis and represents a population estimate
Volume of Distribution Relative to Bioavailability (Vc/F) for Rifapentine (RPT)
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).
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
Clearance Relative to Bioavailability (CLmet/F) for Desacetyl Rifapentine (Des-RPT)
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).
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
Percentage of Participants With Grade 2 Adverse Events (AEs) Judged to be Related to Study Drug Regimen
Time Frame: Measured from study entry through participants' last study visit at 24 weeks after delivery
At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) and were used.
Percentage of Participants With All Serious AEs
Time Frame: Measured from study entry through participants' last study visit at 24 weeks after delivery
At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used.
Percentage of Participants With Related Serious Adverse Events (AEs) in Infants Born to Women Taking Once-weekly RPT + INH
Time Frame: 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.
Incidence of Related Serious Adverse Events (SAEs) in Pregnant and Postpartum Women Taking Once-weekly RPT + INH
Time Frame: Measured from entry through participants' last study visit at 24 weeks after delivery
At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used.
Percentage of Participants With All Grade 3 and 4 AEs
Time Frame: Measured from study entry through participants' last study visit at 24 weeks after delivery
At entry and follow-up, all lab results, sign and symptoms, and diagnoses were recorded. Also, during follow-up grade 2 events related to pregnancy complications, hepatotoxicity, hemorrhage, or peripheral neuropathy, and all grade 3 or events that resulted in discontinuation of study drug regimen, and that met criteria for EAE reporting would further be evaluated and recorded. The DAIDS Table for Grading Adult and Pediatric Adverse Events (V 2.0) and Expedited AE Manual (V 2.0) were used.
Percentage of Participants With All AEs Leading to Permanent Discontinuation of Study Drug Regimen (i.e., RPT, INH, and Pyridoxine)
Time Frame: 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.
Secondary Outcomes
- 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).)
- 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)
- 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).)
- Plasma Concentrations of Rifapentine (RPT) Among Infants(at delivery - (within 3 days of life for infants).)
- 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)
- 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).)
- Cord Blood Concentrations of Rifapentine (RPT) Among Infants(at delivery - (within 3 days of life for infants))
- Cord Blood Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants(at delivery (within 3 days of life for infants).)
- Plasma Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants(at delivery - (within 3 days of life for infants).)
- 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)
- 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).)
- 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).)
- 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).)
- 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).)