Pharmacogenetics-guided Isoniazid Dosing in TB-HIV

NCT05124678 | Unknown Phase 2 DMC

• 1 other identifier: IDI SRC Ref:16/2020
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

The current TB treatment as recommended by World Health Organization (WHO) although capable of achieving 85% cure rates, has limitations, in particular drug interactions, toxicities, and the long treatment duration which increases the possibility of nonadherence. Sub-therapeutic isoniazid concentrations were demonstrated in several studies, including our previous work, carried out among patients with tuberculosis receiving the standard dose (5mg/kg) of isoniazid. The investigators found 78% of patients with HIV had isoniazid concentrations below the recommended threshold. Malabsorption, drug-drug interactions, poor adherence due to high pill burden may contribute to this. Pharmacogenetic variation may compound these factors; isoniazid displays inter-individual variation in serum concentrations and clearance due to differences in individual acetylator status. While patients who metabolize isoniazid slowly (slow acetylators) are at a higher risk of high drug concentrations and toxicities, fast acetylators are more likely to have sub-therapeutic isoniazid concentrations. In other studies, insufficient exposure with isoniazid, one of the cornerstone drugs for TB treatment, has been associated with delayed sputum clearance, development of drug resistance, and treatment failure. Isoniazid is metabolized by the enzyme N-acetyl transferase, which in turn is controlled by the N-acetyl transferase-2 (NAT-2) gene. Polymorphisms in this gene are responsible for the N-acetylation phenotypes, with the distribution of NAT-2 fast, intermediate, and slow acetylators being highly variable especially among African populations. Given that NAT2 acetylator status explains most of the variability in INH exposures, knowledge of NAT2 status may be a simpler way to select the right dose for individual patients. The investigators will therefore provide higher doses to fast acetylators and compare the isoniazid pharmacokinetics in these patients to slow acetylators who receive the standard dose, who are more likely to already be achieving target concentrations.

Conditions

Tuberculosis

Keywords

Pharmacokinetics; Pharmacogenetics; High-dose Isoniazid

Outcome Measures

Primary Outcomes (4)

• Estimate the maximum concentrations of isoniazid stratified by NAT2 group

  Maximum concentrations (Cmax)

  Week 4 of treatment

• Estimate the area under the concentration-time curve of isoniazid stratified by NAT2 group

  Area under the concentration-time curve (AUC)

  Week 4 of treatment

• Estimate the of Clearance isoniazid stratified by NAT2 group

  Clearance (L/h)

  Week 4 of treatment

• Estimate the Volume of distribution of isoniazid stratified by NAT2 group

  Volume of distribution (L)

  Week 4 of treatment

Secondary Outcomes (4)

• Drug-induced hepatotoxicity

  Up to week 8 of treatment

• Other drug-related adverse events

  Up to week 8 of treatment

• Peripheral neuropathy

  Up to week 8 of treatment

• Sputum culture conversion at week 8

  Up to week 8 of treatment

Study Arms (2)

Fast/intermediate acetylators

EXPERIMENTAL

Participants in this arm have fast/intermediate acetylator status from NAT2 genotyping. In the Intensive phase (Month 1-2) of treatment, they will receive; Oral Isoniazid 10mg/kg/day + Rifampicin, Ethambutol and Pyrazinamide at standard dose. In the continuation phase (Month 3 - 6 ) of treatment, they will receive; Oral Isoniazid 5mg/kg/day +Rifampicin at standard dose

Drug: Isoniazid Tablets

Slow acetylators

NO INTERVENTION

Participants in this arm have a slow acetylator status from NAT2 genotyping. They will receive the standard of care. In the Intensive phase (Month 1-2) of treatment, they will receive; Oral Isoniazid 5mg/kg/day + Rifampicin, Ethambutol and Pyrazinamide at standard dose. In the continuation phase (Month 3 - 6 ) of treatment, they will receive; Oral Isoniazid 5mg/kg/day +Rifampicin at standard dose

Interventions

Isoniazid Tablets DRUG

High dose of isoniazid

Also known as: INH

Fast/intermediate acetylators

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study.
• Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
• Age of ≥18 years
• Bacteriologically confirmed pulmonary TB (determined by Xpert, culture, or microscopy)
• Confirmed HIV-1 infection.
• On TB treatment for ≤ 7 days at the time of enrolment (Within this time, the patient is still expected to have mycobacteria present in sputum and will provide enough time to conduct screening procedures)

You may not qualify if:

• TB infection of any organ/systems requiring TB treatment longer than 6 months
• Pregnancy
• Decompensated liver disease and/or aminotransferases \>2.5 x ULN

Sponsors & Collaborators

• Makerere University: lead

Study Sites (1)

Infectious Diseases Institute

Kampala, 256, Uganda

RECRUITING

Related Publications (21)

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• World Health Organization, Guildelines for treatment of Tuberculosis. 2013.

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• Sloan D: Pharmacokinetic Variability in TB Therapy: Associations with HIV and Effect on Outcome. In: Conference on Retroviruses and Opportunistic Infections. Boston, Massachusetts, U.S.A; 2014

  BACKGROUND

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MeSH Terms

Conditions

Tuberculosis

Interventions

Isoniazid

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

Study Officials

• Christine Sekaggya-Wiltshire, MBChB, PhD

  Infectious Diseases Institute-Kampala

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Christine Sekaggya-Wiltshire, MBChB, PhD

CONTACT

256772479791; csekaggya@idi.co.ug

David Meya, MBChB, PhD

CONTACT

256772543730; dmeya@idi.co.ug

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 1, 2021
• First Posted: November 18, 2021
• Study Start: December 7, 2021
• Primary Completion: March 30, 2022
• Study Completion: June 30, 2022
• Last Updated: January 25, 2022

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: 6 months after publication of study results.
• Access Criteria: A direct request shall be made to the investigators .

Locations

UG (1)