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

• Register: ClinicalTrials.gov
• Last refreshed on: 15 November 2021
• Main ID: NCT02651259
• Date of registration: 07/01/2016
• Prospective Registration: Yes
• Primary sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Public title: Evaluating PK, Tolerability, and Safety of Rifapentine and Isoniazid in Pregnant and Postpartum Women
• Scientific 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
• Date of first enrolment: March 13, 2017
• Target sample size: 50
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT02651259
• Study type: Interventional
• Study design: Allocation: Non-Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: None (Open Label).
• Phase: Phase 1/Phase 2

Countries of recruitment

Haiti, Kenya, Malawi, Thailand, United States, Zimbabwe

Contacts

• Name: Jyoti S. Mathad, MD, MSc
• Affiliation: Weill Medical College of Cornell University

Key inclusion & exclusion 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

- 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)



Age minimum: 18 Years
Age maximum: N/A
Gender: Female

Health Condition(s) or Problem(s) studied

Tuberculosis

Intervention(s)

Drug: Rifapentine (RPT)

Dietary Supplement: Pyridoxine (vitamin B6)

Drug: Isoniazid (INH)

Primary Outcome(s)

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).]

Percentage of Participants With All Serious AEs [Time Frame: Measured from study entry through participants' last study visit at 24 weeks after delivery]

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).]

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]

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).]

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]

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]

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)]

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).]

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]

Secondary Outcome(s)

Volume of Distribution of INH [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).]

Maximum Concentration (Cmin) for RPT and Maximum Concentration (Cmin) for Des-RPT Pregnant Women in 2nd and 3rd Trimester [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).]

Number of Participants With Discontinuation of Study Drug Due to Intolerance (Tolerability of Study Drug Regimen - i.e., RPT, INH, and Pyridoxine) [Time Frame: Measured from study entry through participants' last study visit at 24 weeks after delivery]

Clearance Relative to Bioavailability (CL/F) for Rifapentine (RPT) [Time Frame: 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 [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).]

Cord Blood Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants [Time Frame: at delivery (within 3 days of life for infants).]

Number of Infants With Active TB up to 24 Weeks of Life [Time Frame: Measured from birth through participants' last study visit at 24 weeks after delivery]

Plasma Concentrations of Desacetyl Rifapentine (Des-RPT) Among Infants [Time Frame: at delivery - (within 3 days of life for infants).]

Clearance (CL/F) of INH [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).]

Cord Blood Concentrations of Rifapentine (RPT) Among Infants [Time Frame: at delivery - (within 3 days of life for infants)]

Maximum Concentration (Cmax) for RPT Maximum Concentration (Cmax) for Des-RPT Pregnant Women in 2nd and 3rd Trimester [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).]

Plasma Concentrations of Rifapentine (RPT) Among Infants [Time Frame: at delivery - (within 3 days of life for infants).]

Absorption (ka) of INH [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).]

Number of Mothers With Active TB up to 24 Weeks Postpartum [Time Frame: Measured from study entry through participants' last study visit at 24 weeks after delivery]

Secondary ID(s)

12026

IMPAACT 2001

Source(s) of Monetary Support

Please refer to primary and secondary sponsors

Results

• Results available: Yes
• Date Posted: 06/05/2020
• URL: https://clinicaltrials.gov/ct2/show/results/NCT02651259