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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Tuberculosis

Intervention / Treatment
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* Drug: Rifapentine (RPT)
* Drug: Isoniazid (INH)
* Dietary Supplement: Pyridoxine (vitamin B6)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age greater than or equal to 18 years, or minimum age of consent according to locally applicable laws or regulations at screening, verified per site standard operating procedures (SOPs); and able and willing to provide written informed consent for study at screening At screening, evidence by ultrasound of a viable singleton pregnancy with an estimated gestational age at enrollment of greater than or equal to 14 weeks through less than or equal to 34 weeks as per screening ultrasound (see protocol for more information) Had at least one of the following risk factors for TB: Per participant report, the participant was a household contact (see NOTE below) of a known active pulmonary TB patient Per medical records, confirmation of HIV-1 infection (see protocol for more information) and a single positive tuberculin skin test (TST) or interferon gamma release assay (IGRA) at any time in the past. If not available in medical record, perform at screening. NOTE: A household contact was defined as a person who currently lives or lived in the same dwelling unit and shares or shared the same housekeeping arrangements and who reported exposure within the past two years to an adult index case with pulmonary TB. Shared housekeeping arrangements were defined as sleeping under the same roof as the index TB case for at least seven consecutive days during the one month prior to the index case TB diagnosis. Documentation of HIV-1 infection status, or confirmation of HIV-1 infection status (if unknown or undocumented). Confirmation of HIV-1 infection was defined as positive results from two samples (described in the protocol) collected at different time points. All samples tested must be whole blood, serum, or plasma. As this study was being conducted under an IND, all test methods should be FDA-approved, if available. If FDA-approved methods were not available, test methods should be verified according to Good Clinical Laboratory Practice (GCLP) and approved by the IMPAACT Laboratory Center. More information on this criterion was available in the protocol. If HIV-1-infected, documented current prescription of efavirenz (EFV) + 2 nucleoside reverse transcriptase inhibitor (NRTI) regimen and reported taking regimen for at least two weeks prior to enrollment (regimens containing protease, integrase, or entry inhibitors were not permitted) Documented laboratory values obtained within 14 days prior to enrollment: Hemoglobin greater than or equal to 7.5 g/dL White blood cell count greater than or equal to 1500 cells/mm^3 Alanine transaminase (ALT) less than 2.5 times the upper limit of normal (ULN) Total bilirubin less than 1.6 times the ULN Absolute neutrophil count (ANC) greater than or equal to 750 cells/mm^3 Platelet count greater than or equal to 100,000/mm^3 Per participant report at screening, intent to remain in the current geographical area of residence for the duration of the study Per participant report at screening, able to swallow whole tablets Per participant report, intention to keep the pregnancy Per participant report, willingness to permit infant to participate in the study Exclusion Criteria: Evidence of confirmed or probable active TB disease per World Health Organization (WHO) symptom screen and confirmation by Gene Xpert, shielded chest x-ray, or sputum sample Participant report of personal history of INH- or rifampin-resistant, multi-drug resistant (MDR), or extensively drug-resistant (XDR) TB Participant report of personal history of active TB in the past 2 years Participant report of previous treatment for latent tuberculosis infection (LTBI) Household contact (as defined above) with known active MDR or XDR TB disease Known major fetal abnormality as detected on ultrasound Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation Known history of liver cirrhosis at any time prior to study entry Per participant report and/or medical records, evidence of acute clinical hepatitis, such as a combination of abdominal pain, jaundice, dark urine, and/or light stools within 90 days prior to entry Participant report and/or medical records of peripheral neuropathy Grade 2 or higher within 90 days prior to entry Current use or history of active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements Participant report and/or clinical evidence of porphyria Any other condition that, in the opinion of the investigator of record (IoR)/designee, would preclude informed consent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving the study objectives, including taking the study medication Planned or current participation in an interventional drug study Current use of any prohibited or precautionary medications (see protocol for more information), including didanosine (DDI) or stavudine (D4T)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 (pregnant women enrolled in the second trimester)<br>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)<br>* 900 mg of RPT<br>* Other names: Rifamycin;Drug: Isoniazid (INH)<br>* 900 mg of INH<br>* Other names: isonicotinyl hydrazine,;Dietary Supplement: Pyridoxine (vitamin B6)<br>* 25 mg to 100 mg of pyridoxine, based on the current local, national, or international dosing guidelines.<br>* Other names: Vitamin B6;|
| Experimental: Cohort 2 (pregnant women enrolled in the third trimester)<br>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)<br>* 900 mg of RPT<br>* Other names: Rifamycin;Drug: Isoniazid (INH)<br>* 900 mg of INH<br>* Other names: isonicotinyl hydrazine,;Dietary Supplement: Pyridoxine (vitamin B6)<br>* 25 mg to 100 mg of pyridoxine, based on the current local, national, or international dosing guidelines.<br>* Other names: Vitamin B6;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 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). | 
| 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 | 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 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 | 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 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 | 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). | 
| 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. | Measured from entry through participants' last study visit at 24 weeks after delivery | 
| 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. | Measured from study entry through participants' last study visit at 24 weeks after delivery | 
| 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. | Measured from study entry through participants' last study visit at 24 weeks after delivery | 
| 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. | Measured from study entry through participants' last study visit at 24 weeks after delivery | 
| 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. | Measured from study entry through participants' last study treatment dispensation (approximately for 12 weeks) | 
| 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. | Measured from birth through infants' last study visit at 24 weeks after birth | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 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). | 
| 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 | 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 (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 | 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 | 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 | 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). | 
| Cord Blood Concentrations of Rifapentine (RPT) Among Infants | Cord blood concentrations were summarized using using R (version 3.5.1). | at delivery - (within 3 days of life for infants) | 
| Plasma Concentrations of Rifapentine (RPT) Among Infants | Plasma concentrations were summarized using using R (version 3.5.1). | at delivery - (within 3 days of life for infants). | 
| Cord Blood Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants | Cord blood concentrations were summarized using using R (version 3.5.1). | at delivery (within 3 days of life for infants). | 
| Plasma Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants | Plasma blood concentrations were summarized using using R (version 3.5.1). | at delivery - (within 3 days of life for infants). | 
| 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. | Measured from study entry through participants' last study visit at 24 weeks after delivery | 
| 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. | Measured from study entry through participants' last study visit at 24 weeks after delivery | 
| 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. | Measured from birth through participants' last study visit at 24 weeks after delivery | 
| 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) | 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 | 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 | 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 | 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 | 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). |