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Evaluating 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

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ClinicalTrials.gov Identifier: NCT02651259
Recruitment Status : Active, not recruiting
First Posted : January 8, 2016
Last Update Posted : August 1, 2018
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

January 7, 2016
January 8, 2016
August 1, 2018
February 15, 2017
March 31, 2019   (Final data collection date for primary outcome measure)
  • Composite of clearance (CL/F), absorption, and volume of distribution of RPT and its desacetyl-rifapentine metabolite (desRPT) [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
    Based on laboratory evaluations
  • Incidence of related serious adverse events (SAEs) in pregnant and postpartum women taking once-weekly RPT + INH [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
    Severity and laboratory tests will be graded per the DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 2.0.
  • Incidence of Grade 2 adverse events (AEs) judged to be related to study drug regimen [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
    Severity and laboratory tests will be graded per the DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 2.0.
  • Incidence of all Grade 3 and 4 AEs [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
    Severity and laboratory tests will be graded per the DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 2.0.
  • Incidence of all serious AEs [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
    Severity and laboratory tests will be graded per the DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 2.0.
  • Incidence of all AEs leading to permanent discontinuation of study drug regimen (i.e., RPT, INH, and pyridoxine) [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
    Severity and laboratory tests will be graded per the DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 2.0.
  • Incidence of related serious adverse events (AEs) in infants born to women taking once-weekly RPT + INH [ Time Frame: Measured through infants' last study visit at 24 weeks after birth ]
    Severity and laboratory tests will be graded per the DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 2.0.
  • Composite of clearance (CL/F), absorption, and volume of distribution of RPT and its desacetyl-rifapentine metabolite (desRPT) [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
  • Incidence of related serious adverse events (SAEs) in pregnant and postpartum women taking once-weekly RPT + INH [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
  • Incidence of Grade 2 adverse events (AEs) judged to be related to study drug regimen [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
  • Incidence of all Grade 3 and 4 AEs [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
  • Incidence of all serious AEs [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
  • Incidence of all AEs leading to permanent discontinuation of study drug regimen (i.e., RPT, INH, and pyridoxine) [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
  • Incidence of related serious adverse events (AEs) in infants born to women taking once-weekly RPT + INH [ Time Frame: Measured through infants' last study visit at 24 weeks after birth ]
Complete list of historical versions of study NCT02651259 on ClinicalTrials.gov Archive Site
  • Composite of Vd of RPT and desRPT for pregnant women in their second or third trimester [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
    Based on laboratory evaluations
  • Composite of CL/F of RPT and desRPT for pregnant women in their second or third trimester [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
    Based on laboratory evaluations
  • Composite of Ka of RPT and desRPT for pregnant women in their second or third trimester [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
    Based on laboratory evaluations
  • AUC of RPT and desRPT for pregnant women in their second or third trimester [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
    Based on laboratory evaluations
  • Cmax of RPT and desRPT for pregnant women in their second or third trimester [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
    Based on laboratory evaluations
  • Cmin of RPT and desRPT for pregnant women in their second or third trimester [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
    Based on laboratory evaluations
  • RPT concentrations in infants born to women receiving once-weekly RPT + INH [ Time Frame: Measured through infants' last study visit at 24 weeks after birth ]
    Based on laboratory evaluations
  • desRPT concentrations in infants born to women receiving once-weekly RPT + INH [ Time Frame: Measured through infants' last study visit at 24 weeks after birth ]
    Based on laboratory evaluations
  • Permanent discontinuation of study drug regimen due to intolerance (i.e., RPT, INH, and pyridoxine) [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
    Based on laboratory test results, signs, symptoms, and diagnoses
  • Incidence of all AEs leading to permanent discontinuation of study drug regimen (i.e., RPT, INH, and pyridoxine) [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
    Severity and laboratory tests will be graded per the DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 2.0.
  • Incidence of active TB in mother-infant pairs up to 24 weeks postpartum [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
    Based on site-specified confirmatory TB test
  • Composite of CL/F, absorption, and volume of distribution of INH [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
    Based on laboratory evaluations
  • Composite of Vd, CL/F, Ka for pregnant women in their second or third trimester [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
  • RPT concentrations in infants born to women receiving once-weekly RPT + INH [ Time Frame: Measured through infants' last study visit at 24 weeks after birth ]
  • desRPT concentrations in infants born to women receiving once-weekly RPT + INH [ Time Frame: Measured through infants' last study visit at 24 weeks after birth ]
  • Permanent discontinuation of study drug regimen (i.e., RPT, INH, and pyridoxine) [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
  • Incidence of all AEs leading to permanent discontinuation of study drug regimen (i.e., RPT, INH, and pyridoxine) [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
  • RPT concentrations in breast milk of postpartum women receiving once-weekly RPT + INH [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
  • des-RPT concentrations in breast milk of postpartum women receiving once-weekly RPT + INH [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
  • Incidence of active TB in mother-infant pairs up to 24 weeks postpartum [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
  • Composite of CL/F, absorption, and volume of distribution of INH [ Time Frame: Measured through participants' last study visit at 24 weeks after delivery ]
Not Provided
Not Provided
 
Evaluating 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
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
The purpose of this study is to evaluate the pharmacokinetics, 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).

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 will evaluate 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 will enroll HIV-1-infected and HIV-1-uninfected pregnant women with latent TB and their infants into two cohorts based on gestation. Cohort 1 participants will be enrolled in their second trimester (greater than or equal to 14 to less than 28 weeks), and Cohort 2 participants will be enrolled in their third trimester (greater than or equal to 28 to less than or equal to 34 weeks). All participants will receive 12 directly observed once-weekly doses of RPT, INH, and pyridoxine (vitamin B6) at study entry and at 11 weekly follow-up visits. Study researchers will perform an interim analysis during the study, and a dose adjustment may be recommended based on this analysis.

Study visits will occur at days 0-3, once a week through week 11, and once a month until 24 weeks after delivery. Visits will include physical examinations, obstetrical exams, and blood collection. Infants will be followed monthly until 24 weeks after birth.

Interventional
Phase 1
Phase 2
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Tuberculosis
  • Drug: Rifapentine (RPT)
    900 mg of RPT
  • Drug: Isoniazid (INH)
    900 mg of INH
  • Dietary Supplement: Pyridoxine (vitamin B6)
    25 mg to 100 mg of pyridoxine, based on the current local, national, or international dosing guidelines.
  • Experimental: Cohort 1 (pregnant women enrolled in the second trimester)
    Participants will receive 12 directly observed once-weekly doses of RPT, INH, and pyridoxine (vitamin B6) at study entry and at 11 weekly follow-up visits.
    Interventions:
    • Drug: Rifapentine (RPT)
    • Drug: Isoniazid (INH)
    • Dietary Supplement: Pyridoxine (vitamin B6)
  • Experimental: Cohort 2 (pregnant women enrolled in the third trimester)
    Participants will receive 12 directly observed once-weekly doses of RPT, INH, and pyridoxine (vitamin B6) at study entry and at 11 weekly follow-up visits.
    Interventions:
    • Drug: Rifapentine (RPT)
    • Drug: Isoniazid (INH)
    • Dietary Supplement: Pyridoxine (vitamin B6)
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
82
Same as current
March 31, 2019
March 31, 2019   (Final data collection date for primary outcome measure)

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)
  • Has at least one of the following risk factors for TB:

    • Per participant report, the participant is a household contact* 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 is defined as a person who currently lives or lived in the same dwelling unit and shares or shared the same housekeeping arrangements and who reports exposure within the past two years to an adult index case with pulmonary TB. Shared housekeeping arrangements are 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 is 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 is being conducted under an IND, all test methods should be FDA-approved, if available. If FDA-approved methods are 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 is available in the protocol.
  • If HIV-1-infected, documented current prescription of efavirenz (EFV) + 2 nucleoside reverse transcriptase inhibitor (NRTI) regimen and reports taking regimen for at least two weeks prior to enrollment (regimens containing protease, integrase, or entry inhibitors are 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 1,500 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)
Sexes Eligible for Study: Female
18 Years and older   (Adult, Older Adult)
Yes
Contact information is only displayed when the study is recruiting subjects
Haiti,   Kenya,   Malawi,   Thailand,   Zimbabwe
United States
 
NCT02651259
IMPAACT 2001
12026 ( Registry Identifier: DAIDS-ES )
Yes
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Not Provided
National Institute of Allergy and Infectious Diseases (NIAID)
National Institute of Allergy and Infectious Diseases (NIAID)
Not Provided
Study Chair: Jyoti S. Mathad, MD, MSc Weill Medical College of Cornell University
National Institute of Allergy and Infectious Diseases (NIAID)
July 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP