Point-of-care Pharmacogenomic Testing to Optimize Isoniazid Dosing for Tuberculosis Prevention

NCT05413551 | Completed Phase 1 Results

• 2 other identifiers: 658081R21AI172182-01
• Study Type: interventional
• Target: 78
• Locations: 1 country
• Sites: 1

Brief Summary

This trial is designed to determine whether modifying the dose of isoniazid for individuals according to their n-acetyltransferase 2 (NAT2) genotype could increase the probability of achieving equivalence of area-under-the-curve.

Conditions

Tuberculosis Infection; Isoniazid Adverse Reaction

Outcome Measures

Primary Outcomes (2)

• Isoniazid Plasma Area-under-the-curve

  Area under the plasma concentration-time curve over 24 hours (AUC₀-₂₄) for isoniazid, estimated using a population pharmacokinetic model based on plasma concentrations collected at 1, 2, 8, and 24 hours post-dose on Days 7 and 14.

  Days 7 and 14 (1, 2, 8, and 24 hours post-dose)

• Isoniazid Clearance

  Apparent clearance (CL) of isoniazid estimated from a population pharmacokinetic model using plasma concentration data collected at 1, 2, 8, and 24 hours post-dose on Days 7 and 14. Clearance values represent model-derived population parameter estimates. Data across the day 7 and day 14 time points are combined to provide an estimated value as a model parameter, representing the typical value per group.

  Days 7 and 14 (1, 2, 8, and 24 hours post-dose)

Secondary Outcomes (2)

• Maximum Isoniazid Concentration (Cmax)

  Days 7 and 14 (1, 2, 8, and 24 hours post-dose)

• Isoniazid Concentration at 24 Hours

  Days 7 and 14 (24 hours post-dose)

Study Arms (3)

Rapid acetylator

EXPERIMENTAL

Participants will receive 1 standard dose (Day 0), followed by 1 higher dose (Day 7), follow by 2 standard doses (Days 14 and 21).

Drug: Standard dose of isoniazid; Drug: High-dose isoniazid

Intermediate acetylator

ACTIVE COMPARATOR

Participants will receive 4 standard doses (Days 0, 7, 14 and 21).

Drug: Standard dose of isoniazid

Slow acetylator

EXPERIMENTAL

Participants will receive 2 standard doses (Days 0 and 7), followed by 1 lower dose (Day 21), follow by 1 standard dose (Day 21).

Drug: Low-dose isoniazid; Drug: Standard dose of isoniazid

Interventions

Low-dose isoniazid DRUG

Pharmacogenomic-modified dose of isoniazid - 5 mg/kg oral tablet (maximum 300 mg)

Slow acetylator

Standard dose of isoniazid DRUG

15 mg/kg oral tablet (up to 900 mg)

Intermediate acetylator; Rapid acetylator; Slow acetylator

High-dose isoniazid DRUG

Pharmacogenomic-modified dose of isoniazid - 25 mg/kg oral tablet (maximum 1500 mg)

Rapid acetylator

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Eligible for latent tuberculosis treatment by Brazil's national guidelines\*
• provides written informed consent to participate in the study

You may not qualify if:

• Evidence of active tuberculosis or currently under evaluation for active tuberculosis
• Receiving drugs that interact with Rifapentine (e.g. methadone, warfarin)
• Known intolerance or hypersensitivity to isoniazid or rifapentine
• Prior treatment for active or latent tuberculosis \> 14 days
• Close contact to isoniazid- or rifampicin-resistant tuberculosis (TB) case
• Neutropenia (absolute neutrophil count \<1000 cells/mm3)
• Clinical diagnosis of active liver disease or alcohol dependence
• alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>3 times the upper limit of normal

Sponsors & Collaborators

• Fiocruz Mato Grosso do Sul: collaborator
• Stanford University: lead
• Federal University of Mato Grosso: collaborator
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (1)

Federal University of Mato Grosso do Sul

Campo Grande, Mato Grosso do Sul, Brazil

Location

Related Publications (1)

• Verma R, Patil S, Zhang N, Moreira FMF, Vitorio MT, Santos ADS, Wallace E, Gnanashanmugam D, Persing DH, Savic RM, Croda J, Andrews JR. A Rapid Pharmacogenomic Assay to Detect NAT2 Polymorphisms and Guide Isoniazid Dosing for Tuberculosis Treatment. Am J Respir Crit Care Med. 2021 Dec 1;204(11):1317-1326. doi: 10.1164/rccm.202103-0564OC.

  PMID: 34375564 BACKGROUND

MeSH Terms

Conditions

Latent Tuberculosis

Interventions

Isoniazid

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Latent Infection

Intervention Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Jason Andrews, Professor
• Organization: Stanford University

jandr@stanford.edu

+16504972679

Study Officials

• Jason R Andrews, MD

  Stanford University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Study Record Dates

• First Submitted: June 7, 2022
• First Posted: June 10, 2022
• Study Start: March 23, 2023
• Primary Completion: April 23, 2025
• Study Completion: June 25, 2025
• Last Updated: June 15, 2026
• Results First Posted: June 15, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR

Locations

BR (1)