Clinical Trials Logo

Clinical Trial 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.

Clinical Trial 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 Design

Related Conditions & MeSH terms

NCT number NCT05124678
Study type Interventional
Source Makerere University
Contact Christine Sekaggya-Wiltshire, MBChB, PhD
Phone 256772479791
Email [email protected]
Status Not yet recruiting
Phase Phase 2
Start date November 18, 2021
Completion date June 30, 2022

See also
  Status Clinical Trial Phase
Recruiting NCT04369326 - Community Initiated Preventive Therapy for TB N/A
Completed NCT02337270 - Phase 1 Clinical Trial of the Safety and Immunogenicity of an Adenovirus-based TB Vaccine Administered by Aerosol Phase 1
Recruiting NCT04271397 - Immunological Biomarkers in Tuberculosis Management N/A
Withdrawn NCT03639038 - Tuberculosis Diagnosis by Flow Cytometry
Completed NCT03199313 - Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Sutezolid Phase 1
Recruiting NCT03767946 - Epidemiological Study In Tuberculosis-Endemic Urban Area in Senegal
Recruiting NCT04463680 - Rifampin and the Contraceptive Implant Phase 4
Completed NCT03973970 - Assessing the Ability of the T-SPOT®.TB Test (IQ)
Completed NCT04874948 - Absorption, Elimination and Safety of 14C-labeled Radioactive BTZ-043, a New Compound in TB Treatment Phase 1
Not yet recruiting NCT04738812 - Determination of Adequate Tuberculosis Regimen in Patients Hospitalized With HIV-associated Severe Immune Suppression Phase 3
Active, not recruiting NCT02715271 - Study of TB Lesions Obtained in Therapeutical Surgery
Completed NCT02781909 - Potential Efficacy and Safety of Using Adjunctive Ibuprofen for XDR-TB Tuberculosis Phase 2
Recruiting NCT02807025 - Nasal, Tracheal and Bronchial Mucosal Lining Fluid(MLF) Sampling From Patients With Respiratory Diseases N/A
Completed NCT02729571 - Dose-escalation Safety and Immunogenicity Study to Compare MTBVAC to BCG in Newborns With a Safety Arm in Adults Phase 1/Phase 2
Completed NCT02536768 - Evaluation of South Africa's National Adherence Strategy N/A
Terminated NCT02532036 - MVA85A Aerosol vs Intramuscular Vaccination in Adults With Latent Mycobacterium Tuberculosis (M. tb) Infection Phase 1
Completed NCT02774993 - Doxycycline in Human Pulmonary Tuberculosis Phase 2
Completed NCT01934309 - Do Clinical Decision-support Reminders for Medical Providers Improve the Do Clinical Decision-support Reminders for Medical Providers Improve the Prevalence of IPT Initiation Among HIV Positive Adults in Western Kenya? N/A
Completed NCT01408914 - Trial of High-Dose Rifampin in Patients With TB Phase 2
Completed NCT01674218 - Effect of PA-824 and of PA-824 Plus Moxifloxacin on the QTc Interval in Healthy Volunteers Phase 1