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

NCT03800381 | Completed

• 2 other identifiers: IRB201801820 - HRZ PK -N5R01HD071779-11
• Study Type: observational
• Target: 92
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Tuberculosis; Human Immunodeficiency Virus; Coinfection

Keywords

Pharmacokinetic; Pharmacogenomic; Antituberculosis drugs; Children; Tuberculosis; TB/HIV coinfection

Outcome Measures

Primary Outcomes (4)

• Peak concentration (Cmax) of isoniazid, rifampin and pyrazinamide in the new pediatric HRZ FDC tablet.

  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.

  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

  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.

  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 Outcomes (4)

• AUC0-8h of isoniazid, rifampin and pyrazinamide in the new versus old pediatric HRZ FDC tablet.

  After at least 4 weeks of anti-TB therapy

• Cmax of isoniazid, rifampin and pyrazinamide in the new versus old pediatric HRZ FDC tablet.

  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.

  After at least 4 weeks of anti-TB therapy

• Identify optimal weight-band dosages of the new HRZ FDC tablet

  After at least 4 weeks of anti-TB therapy

Study Arms (2)

Active TB only

Children with clinical diagnosis or acid-fast bacilli (AFB) smear positive TB disease

Other: Observational PK study

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

Interventions

Observational PK study OTHER

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.

Also known as: New pediatric isoniazid/rifampin/pyrazinamide (HRZ) FDC tablet

Active TB only; Active TB with HIV Co-infection

Eligibility Criteria

• Age: 3 Months - 14 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)
• Sampling Method: Non-Probability Sample

Study Population

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

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Florida: lead
• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): collaborator

Study Sites (1)

Kwame Nkrumah University of Science and Technology

Kumasi, Ghana

Location

Biospecimen

Retention: SAMPLES WITH DNA

Ethylenediaminetetraacetic acid (EDTA) plasma and whole blood deoxyribonucleic acid (DNA)

MeSH Terms

Conditions

Tuberculosis; Acquired Immunodeficiency Syndrome; Coinfection

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; HIV Infections; Blood-Borne Infections; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Slow Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Study Officials

• Awewura Kwara, MD

  University of Florida

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 3, 2019
• First Posted: January 11, 2019
• Study Start: January 28, 2019
• Primary Completion: August 31, 2024
• Study Completion: August 31, 2024
• Last Updated: November 25, 2024

Record last verified: 2024-11

Locations

GH (1)