Pharmacogenetics-guided Isoniazid Dosing in TB-HIV (PHINX)

January 19, 2022 updated by: Makerere University

A Phase II Trial to Describe the Pharmacokinetics, Safety and Efficacy of Pharmacogenetics-guided Dosing of Isoniazid in Patients With HIV-associated TB

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

N-acetyl transferase genotyping will be performed on HIV infected patients diagnosed with T B. Slow acetylators will be initiated on the standard dose of isoniazid (5mg/kg) while fast and intermediate acetylators will be initiated on 10mg/kg of isoniazid. All other TB drugs will be given at their standard doses.

Monitoring for toxicities will be performed every two weeks (including ALT and screening for peripheral neuropathy) and isoniazid concentrations will be measured four weeks after initiating treatment at Ohr, 30mins, 1 hr, Thr and 4hr following observed drug intake.

Patients will be continued on standard dose isoniazid after completing the first 8 weeks of treatment (intensive phase).

Sputum cultures for mycobacteria will be performed at baseline, week 2, 4 and week 8. TB treatment outcome will be assessed after 6 months of treatment.

Non-linear mixed effects modelling will be used to model PK-PD data taking into account clinical and demographic factors like age, sex and BMI. The investigators will develop a model to establish the population parameters for isoniazid (for example clearance, absorption rate constant and volume of distribution) and the variability around these primary PK parameters. The investigators will then use the model to derive secondary PK parameters, namely area under the concentration-time curve (AUC) and maximum concentrations (Cmax) of isoniazid for each participant. The investigators will compare the PK parameters of isoniazid in fast/intermediate acetylators taking 10mg/kg and slow acetylators taking 5mg/kg of isoniazid.

In addition to the main objectives of the study, the investigators will also compare the PK in patients in the PG guided isoniazid dosing group to those in the historical cohort while matching for NAT2 status, age and sex. In the historical cohort, NAT-2 acetlyator genotyping was performed but patients received standard dosing regardless of NAT-2 acetylator status. In this trial, the investigators will use pharmacogenetic guided therapy for all participants. The investigators will therefore be able to compare the pharmacokinetic data above, safety and efficacy in patients who received pharmacogenetic therapy and those who did not.

The investigators will use PK-PD models to describe the relationship between concentrations and pharmacodynamic data (including toxicities and sputum conversion at week 8) in patients on the different doses. In addition to this, the investigators will also make this same comparison for patients in this study and those who did not receive PG guided therapy from the historical cohort. The investigators will also compare the number of grade 3-5 adverse events and time to sputum culture conversion in patients in patients who did and did not receive PG guided therapy while matching for NAT2 status, age and sex

Study Type

Interventional

Enrollment (Anticipated)

40

Phase

  • Phase 2

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

  • Name: Christine Sekaggya-Wiltshire, MBChB, PhD
  • Phone Number: 256772479791
  • Email: csekaggya@idi.co.ug

Study Contact Backup

  • Name: David Meya, MBChB, PhD
  • Phone Number: 256772543730
  • Email: dmeya@idi.co.ug

Study Locations

  • Uganda
      • Kampala, Uganda, 256
        • Recruiting
        • Infectious Diseases Institute
        • Contact:
        • Principal Investigator:
          • Christine Sekaggya-Wiltshire, MBChB, PhD

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

18 years to 90 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • 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)

Exclusion Criteria:

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

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

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Fast/intermediate acetylators

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
High dose of isoniazid
Other Names:
  • INH
No Intervention: Slow acetylators

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Estimate the maximum concentrations of isoniazid stratified by NAT2 group
Time Frame: Week 4 of treatment
Maximum concentrations (Cmax)
Week 4 of treatment
Estimate the area under the concentration-time curve of isoniazid stratified by NAT2 group
Time Frame: Week 4 of treatment
Area under the concentration-time curve (AUC)
Week 4 of treatment
Estimate the of Clearance isoniazid stratified by NAT2 group
Time Frame: Week 4 of treatment
Clearance (L/h)
Week 4 of treatment
Estimate the Volume of distribution of isoniazid stratified by NAT2 group
Time Frame: Week 4 of treatment
Volume of distribution (L)
Week 4 of treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Drug-induced hepatotoxicity
Time Frame: Up to week 8 of treatment
Grade 2 or higher elevation in ALT or total bilirubin (drug-induced hepatotoxicity)
Up to week 8 of treatment
Other drug-related adverse events
Time Frame: Up to week 8 of treatment
Other grade 2 or higher adverse events
Up to week 8 of treatment
Peripheral neuropathy
Time Frame: Up to week 8 of treatment
Grade 2 or higher peripheral neuropathy
Up to week 8 of treatment
Sputum culture conversion at week 8
Time Frame: Up to week 8 of treatment
Proportion of patients who remain sputum positive
Up to week 8 of treatment

Collaborators and Investigators

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

Sponsor

Makerere University

Investigators

  • Principal Investigator: Christine Sekaggya-Wiltshire, MBChB, PhD, Infectious Diseases Institute-Kampala

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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)

December 7, 2021

Primary Completion (Anticipated)

March 30, 2022

Study Completion (Anticipated)

June 30, 2022

Study Registration Dates

First Submitted

October 1, 2021

First Submitted That Met QC Criteria

November 17, 2021

First Posted (Actual)

November 18, 2021

Study Record Updates

Last Update Posted (Actual)

January 25, 2022

Last Update Submitted That Met QC Criteria

January 19, 2022

Last Verified

October 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • IDI SRC Ref:16/2020

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Individual patient data (IPD) will made available to other researchers for further analysis or met-analysis upon reasonable request to the investigators.

IPD Sharing Time Frame

6 months after publication of study results.

IPD Sharing Access Criteria

A direct request shall be made to the investigators .

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

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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