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

NCT02651259 | Completed Phase 1 Results DMC FDA Drug

• 2 other identifiers: IMPAACT 200112026
• Study Type: interventional
• Target: 50
• Locations: 5 countries
• Sites: 5

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).

Conditions

Tuberculosis

Outcome Measures

Primary Outcomes (10)

• 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 Outcomes (14)

• 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).

• 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).

• 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).

• 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).

• Cord Blood Concentrations of Rifapentine (RPT) Among Infants

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

Study Arms (2)

Cohort 1 (pregnant women enrolled in the second trimester)

EXPERIMENTAL

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)

Cohort 2 (pregnant women enrolled in the third trimester)

EXPERIMENTAL

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

Rifapentine (RPT) DRUG

900 mg of RPT

Also known as: Rifamycin

Cohort 1 (pregnant women enrolled in the second trimester); Cohort 2 (pregnant women enrolled in the third trimester)

Isoniazid (INH) DRUG

900 mg of INH

Also known as: isonicotinyl hydrazine,

Cohort 1 (pregnant women enrolled in the second trimester); Cohort 2 (pregnant women enrolled in the third trimester)

Pyridoxine (vitamin B6) DIETARY_SUPPLEMENT

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

Also known as: Vitamin B6

Cohort 1 (pregnant women enrolled in the second trimester); Cohort 2 (pregnant women enrolled in the third trimester)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (5)

Les Centres GHESKIO Clinical Research Site (GHESKIO-INLR) CRS

Port-au-Prince, HT-6110, Haiti

Location

Kenya Medical Research Institute / Walter Reed Project Clinical Research Center, Kericho CRS

Kericho, 20200, Kenya

Location

Malawi CRS

Lilongwe, Central Malawi, Malawi

Location

Siriraj Hospital ,Mahidol University NICHD CRS

Bangkok, Bangkoknoi, 10700, Thailand

Location

Harare Family Care CRS

Harare, Zimbabwe

Location

Related Publications (1)

• 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.

  PMID: 34323955 DERIVED

Related Links

• Severity and laboratory tests will be graded per the DAIDS Table for Grading Adult and Pediatric Adverse Events, Version 2.0(dated November 2014 available on the RSC website)
• Requirements, definitions and methods for expedited reporting of adverse events (AEs) are outlined in Version 2.0 of the DAIDS EAE Manual

MeSH Terms

Conditions

Tuberculosis

Interventions

rifapentine; rifamycin SV; Isoniazid; Pyridoxine; Vitamin B 6

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Hydrazines; Organic Chemicals; Isonicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring; Picolines

Results Point of Contact

• Title: Melissa Allen, Director, IMPAACT Operations Center
• Organization: Family Health International (FHI 360

mallen@fhi360.org

(919) 405-1429

Study Officials

• Jyoti S. Mathad, MD, MSc

  Weill Medical College of Cornell University

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 7, 2016
• First Posted: January 8, 2016
• Study Start: March 13, 2017
• Primary Completion: April 10, 2019
• Study Completion: April 10, 2019
• Last Updated: November 4, 2021
• Results First Posted: May 6, 2020

Record last verified: 2020-05

Locations

TH (1); MA (1); HA (1); ZI (1); KE (1)