The Individualized M(X) Drug-resistant TB Treatment Strategy Study
- Conditions
- Tuberculosis, Multidrug-Resistant
- Interventions
- Drug: Individualized TB treatment with multiple drugsDrug: Standardized TB treatment with multiple drugs
- Registration Number
- NCT03237182
- Brief Summary
This is a randomized controlled clinical trial comparing treatment success of a gene-derived individualized drug-resistant Tuberculosis regimen to a standard Tuberculosis regimen based on South African National Tuberculosis guidelines.
- Detailed Description
When drug resistance is detected by molecular methods such as the Xpert MTB/RIF assay, second-line Multi Drug-Resistant (MDR) Tuberculosis treatment is started in the complete absence of detailed resistance information. The diagnosis of Multi Drug-Resistant Tuberculosis is confirmed only on availability of Line Probe Assay (LPA)/Drug Susceptibility Testing (DST) results. Extremely Drug-Resistant (XDR) Tuberculosis is diagnosed by in vitro phenotypic resistance to Rifampicin, Isoniazid, fluoroquinolones and injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin). Existing culture based Drug Susceptibility Testing provides results after 6-8 weeks. This duration may be further increased by other existing laboratory challenges, such as culture contamination.
Furthermore, initial regimens are often not optimal and sometimes completely ineffective as there is a lack of Drug Susceptibility Testing to support them. More importantly, even optimal regimens are changed due to patient intolerance of the drug's side effects.
Whole Genome Sequencing (WGS) has the advantage of determining the complete Deoxyribonucleic acid (DNA) sequence of an organism's genome at a single time point. Using this technology, genotypic mutations conferring resistance to anti-tuberculosis drugs can be identified. This information will assist in identifying not only potential resistant drugs, but also susceptible drugs and thus enable a more accurate and appropriate choice of regimen. In addition, drugs that will not add value to the treatment outcome, but will increase rates of adverse drug reactions, can be eliminated earlier, improving drug-resistant TB treatment outcomes.
In this proposal, we aim to use Mycobacterium Tuberculosis (MTB) whole genome sequencing prior to the selection of a drug-resistant tuberculosis treatment regimen and thus provide an individualized treatment strategy for drug-resistant tuberculosis. By adopting this method, we hope to improve culture negative survival rates at 6 months post treatment initiation .
This study will include 448 adult patients (age ≥ 18 years) that meet inclusion criteria. Patients referred by provincial satellite facilities with microbiological confirmation of drug-resistant tuberculosis (e.g. Xpert MTB/RIF assay / Line Probe Assay) to King DinuZulu Hospital (KDH) will be recruited. Patients randomized to the control arm will receive standard of care (SOC) treatment. Patients randomized to the intervention arm will be given an individualized treatment regimen based on whole genome sequencing conducted on Mycobacteria Growth Indicator Tube (MGIT) positive sputum samples collected at the screening visit.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 205
Not provided
- Persons suffering from any serious acute condition.
- Any other chronic or clinically significant medical condition that in the opinion of the attending clinician would render the patient unsuitable for participation in the study.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Individualized treatment for drug resistant tuberculosis Individualized TB treatment with multiple drugs Patients with drug resistance will have whole genome sequencing performed on the respective positive MGIT sample. An individualized TB treatment regimen will be provided to patients based on the whole genome sequencing results Standard treatment regimen for drug resistant tuberculosis Standardized TB treatment with multiple drugs As per South African Department of Health Standard of Care for the treatment of drug resistant tuberculosis
- Primary Outcome Measures
Name Time Method Culture negative survival rate 30 months To determine if a gene-derived individualized treatment approach in patients with drug-resistant TB will improve culture negative survival rates at 6 months post treatment initiation
- Secondary Outcome Measures
Name Time Method Characterization of multi drug-resistant tuberculosis strains 30 months The minimum inhibitory concentrations of Mtb isolates will be correlated with the genotypic mutations detected and the evolution of drug resistance will be monitored by comparing serial isolates from patients
Measure of adherence 30 months To compare adherence to DR-TB drugs using drug concentrations in DBS samples, hair samples, pill count data and participant self-report
Rates of adverse events 30 months Rates of adverse events will be compared between arms
Tuberculosis treatment outcomes 30 months Treatment outcomes are based on treatment success (cure rates and completion of treatment) or mortality or retention in care or time to culture conversion
Drug Concentration 30 months To determine the drug concentrations and long-term drug exposures to DR-TB drug regimens in DBS and hair samples respectively
Improved assessment and management of DR-TB 30 months Development of an optimized method for extraction of MTB DNA directly from sputum samples for WGS, compare resistance mutations detected by WGS to current Xpert and LPA; to design a clinical decision-making algorithm for assessment and management of detected resistance mutations
Evolution of HIV drug resistance 30 months To assess the evolution of HIV drug resistance in patients receiving Bedaquiline and ART for HIV/MDR-TB treatment
Trial Locations
- Locations (1)
King Dinuzulu Hospital
🇿🇦Durban, Kwa-Zulu Natal, South Africa