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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

This study is currently recruiting participants.
Verified October 2017 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
ClinicalTrials.gov Identifier:
NCT02651259
First Posted: January 8, 2016
Last Update Posted: October 3, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
  Purpose
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).

Condition Intervention Phase
Tuberculosis Drug: Rifapentine (RPT) Drug: Isoniazid (INH) Dietary Supplement: Pyridoxine (vitamin B6) Phase 1 Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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 ]
    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 (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.

  • 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 ]
    Based on breast milk PK sample collection

  • 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 ]
    Based on breast milk PK sample collection

  • 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


Estimated Enrollment: 82
Actual Study Start Date: February 15, 2017
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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) during their study visits at weeks 1-12.
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 2 (pregnant women enrolled in the third trimester)
Participants will receive 12 directly observed once-weekly doses of RPT, INH, and pyridoxine (vitamin B6) during their study visits at weeks 1-12.
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.

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 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) during their study visits at weeks 1-12. 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 for weeks 1-12, 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.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
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)
  • 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)
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02651259


Locations
United States, New York
Bronx-Lebanon Hospital Center NICHD CRS Recruiting
The Bronx, New York, United States, 10457
Contact: Martha Cavallo, A.N.P., C.R.N.P.    718-960-1010    mcavallo@bronxleb.org   
Haiti
Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS Recruiting
Port-au-Prince, Haiti, HT-6110
Contact: Cynthia Riviere, M.D.    509-22222241    criviere@gheskio.org   
Kenya
Kenya Medical Research Institute / Walter Reed Project Clinical Research Center, Kericho CRS Recruiting
Kericho, Kenya, 20200
Contact: Samwel K. Chirchir, R.N., B.Sc.    254-522-030388    Samwel.Chirchir@usamru-k.org   
Malawi
Malawi CRS Recruiting
Lilongwe, Central Malawi, Malawi
Contact: Deborah D. Kamwendo    265-888-251778    kamwendo@email.unc.edu   
Thailand
Siriraj Hospital ,Mahidol University NICHD CRS Recruiting
Bangkok, Bangkoknoi, Thailand, 10700
Contact: Watcharee Lermankul    66-2-4197000 ext 5695    watchareeped@gmail.com   
Zimbabwe
Harare Family Care CRS Recruiting
Harare, Zimbabwe
Contact: Sukunena J. Maturure, RGN    263-712437682    sjmaturure@uzcrc.co.zw   
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
Study Chair: Jyoti S. Mathad, MD, MSc Weill Medical College of Cornell University
  More Information

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT02651259     History of Changes
Other Study ID Numbers: IMPAACT 2001
12026 ( Registry Identifier: DAIDS-ES )
First Submitted: January 7, 2016
First Posted: January 8, 2016
Last Update Posted: October 3, 2017
Last Verified: October 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Tuberculosis
Latent Tuberculosis
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Vitamins
Vitamin B 6
Pyridoxal
Pyridoxine
Vitamin B Complex
Isoniazid
Rifapentine
Rifampin
Micronutrients
Growth Substances
Physiological Effects of Drugs
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents
Fatty Acid Synthesis Inhibitors
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Antibiotics, Antitubercular
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Cytochrome P-450 CYP2B6 Inducers