Adequacy of the New Pediatric Isoniazid/Rifampin/Pyrazinamide (HRZ) Tablet

December 6, 2023 updated by: University of Florida

Pharmacokinetics of Anti-tuberculosis and Antiretroviral Drugs in Children

Lack of quality-assured pediatric formulations of the first-line antituberculosis (anti-TB) drugs is barrier to optimized tuberculosis (TB) treatment outcome in children. In 2010 and subsequently modified in 2014, the World Health Organization (WHO) recommended increased dosages of the first-line anti-TB drugs for children, but there were no child-friendly fixed-dose combination (FDC) formulations based on the guidelines. A large proportion of children treated with the new guidelines using old formulations did not achieve the desired rifampin peak concentration (Cmax) > 8 mg/L and pyrazinamide Cmax > 35 mg/L. The TB Alliance and the WHO led the development of a new child-appropriate isoniazid/rifampin/pyrazinamide (HRZ) and isoniazid/rifampin (HR) FDC formulation in line with current WHO recommended dosing guidelines. The new formulations dissolve quickly in liquid, have palatable fruit flavors, and are expected to improved daily adherence but no studies have evaluated the pharmacokinetics (PK) of the FDC formulation in children. The study team hypothesize that the new dispersible HRZ FDC tablet, dosed according to current WHO weight-band dosing recommendations will result in better PK parameters for each drug component than that achieved by the old formulation.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

This study will evaluate the PK of the new pediatric HRZ FDC tablet in Ghanaian children with TB with and without HIV coinfection. The new HRZ FDC dispersible tablet was designed to be child-friendly and to achieve recommended dosages for each weight-band. The formulation has been rolled out in Africa without PK studies in the target population to verify that the tablets achieves adequate drug concentrations. The current study will evaluate the adequacy of the formulation by examining the PK of the component drugs as well as the effect of HIV coinfection. The direct PK data will be used in a population PK model and stimulations to define optimal weight-band dosages and proportions of the components of the pediatric FDC tablets.

Study Type

Observational

Enrollment (Estimated)

92

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Ghana
      • Kumasi, Ghana
        • Recruiting
        • Kwame Nkrumah University of Science and Technology
        • Contact:
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 year to 12 years (Child)

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Children aged 3 months to14 years with active TB with or without HIV co-infection

Description

Inclusion Criteria:

  • Children with active TB with or without HIV coinfection. Active TB diagnosis defined by clinical criteria consistent with active TB and/or a positive AFB smear.
  • Available for follow-up until completion of TB treatment and/or achievement of a study endpoint like discontinuation of therapy, and/or pharmacokinetic sampling.

Exclusion Criteria:

  • Children with concurrent conditions other than HIV, have acute hepatitis within 30 days of study entry, persistent vomiting, and diarrhea will be excluded from the study.
  • Unable to obtain informed signed consent from parent(s) or legal guardian.
  • Have AIDS-related opportunistic infections other than TB, history of or proven acute hepatitis within 30 days of study entry, persistent vomiting, or diarrhea.
  • Hemoglobin < 6 g/dl, white blood cells < 2500/mm3, serum creatinine > 1.5 mg/dl, aspartate transaminase (AST) and alanine transaminase (ALT) > 2 times upper limit of normal.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Active TB only
Children with clinical diagnosis or acid-fast bacilli (AFB) smear positive TB disease
Other: Observational PK study
The study team will examine the PK and tolerability of the new HRZ 50/75/150 mg dispersible tablet in children with TB with and without HIV coinfection. Intensive PK testing will be performed after at least 4 weeks of treatment in children on first-line anti-TB therapy using the new pediatric HRZ FDC tablet.
Other Names:
  • New pediatric isoniazid/rifampin/pyrazinamide (HRZ) FDC tablet
Active TB with HIV Co-infection
Children with clinical diagnosis or AFB smear positive TB disease who test positive for HIV infection
Other: Observational PK study
The study team will examine the PK and tolerability of the new HRZ 50/75/150 mg dispersible tablet in children with TB with and without HIV coinfection. Intensive PK testing will be performed after at least 4 weeks of treatment in children on first-line anti-TB therapy using the new pediatric HRZ FDC tablet.
Other Names:
  • New pediatric isoniazid/rifampin/pyrazinamide (HRZ) FDC tablet

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Peak concentration (Cmax) of isoniazid, rifampin and pyrazinamide in the new pediatric HRZ FDC tablet.
Time Frame: After at least 4 weeks of anti-TB therapy
Mean and median Cmax of rifampin, isoniazid and pyrazinamide in children with TB treated with the new HRZ FDC tablet.
After at least 4 weeks of anti-TB therapy
Area under the time-concentration curve from 0-8 hours (AUC0-8h) of isoniazid, rifampin and pyrazinamide in the new pediatric HRZ FDC tablet.
Time Frame: After at least 4 weeks of anti-TB therapy
Mean and median AUC0-8h of rifampin, isoniazid and pyrazinamide in children with TB treated with the new HRZ FDC tablet.
After at least 4 weeks of anti-TB therapy
Cmax of isoniazid, rifampin and pyrazinamide in children with TB with and without HIV coinfection
Time Frame: After at least 4 weeks of anti-TB therapy
Geometric mean values of Cmax of rifampin, isoniazid and pyrazinamide in children with HIV/TB coinfection compared to those with TB alone.
After at least 4 weeks of anti-TB therapy
AUC0-8h of isoniazid, rifampin and pyrazinamide in children with TB with and without HIV coinfection.
Time Frame: After at least 4 weeks of anti-TB therapy
Geometric mean values of AUC0-8h of rifampin, isoniazid and pyrazinamide in children with HIV/TB coinfection compared to those with TB alone.
After at least 4 weeks of anti-TB therapy

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
AUC0-8h of isoniazid, rifampin and pyrazinamide in the new versus old pediatric HRZ FDC tablet.
Time Frame: After at least 4 weeks of anti-TB therapy
Geometric mean values of AUC0-8h of rifampin, isoniazid, and pyrazinamide in children with TB treated with the new FDC tablet compared to those treated with the old formulation in our previous study (historical controls).
After at least 4 weeks of anti-TB therapy
Cmax of isoniazid, rifampin and pyrazinamide in the new versus old pediatric HRZ FDC tablet.
Time Frame: After at least 4 weeks of anti-TB therapy
Geometric mean values of Cmax of rifampin, isoniazid, and pyrazinamide in children with TB treated with the new FDC tablet compared to those treated with the old formulation in our previous study (historical controls).
After at least 4 weeks of anti-TB therapy
Proportion of children treated with new pediatric HRZ FDC tablet who develop with liver enzymes elevations.
Time Frame: After at least 4 weeks of anti-TB therapy
Frequency of liver enzymes elevations compared to baseline requiring treatment modification in children with TB with and without HIV coinfection.
After at least 4 weeks of anti-TB therapy
Identify optimal weight-band dosages of the new HRZ FDC tablet
Time Frame: After at least 4 weeks of anti-TB therapy
Use a population PK model that incorporates demographic, clinical and genetic factors and stimulations to identify the optimal weight-band dosing of the new FDC formulation.
After at least 4 weeks of anti-TB therapy

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Florida

Collaborators

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

  • Principal Investigator: Awewura Kwara, MD, University of Florida

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

January 28, 2019

Primary Completion (Estimated)

August 31, 2024

Study Completion (Estimated)

August 31, 2024

Study Registration Dates

First Submitted

January 3, 2019

First Submitted That Met QC Criteria

January 8, 2019

First Posted (Actual)

January 11, 2019

Study Record Updates

Last Update Posted (Actual)

December 7, 2023

Last Update Submitted That Met QC Criteria

December 6, 2023

Last Verified

December 1, 2022

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IRB201801820 - HRZ PK -N
  • 5R01HD071779-11 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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