The Individualized M(X) Drug-resistant TB Treatment Strategy Study

Tuberculosis, Multidrug-Resistant Clinical Trial

— InDEX  

Official title:

The Individualized M(X) Drug-resistant TB Treatment Strategy Study A Strategy to Improve Treatment Outcomes in Patients With Drug-resistant TB

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03237182
• Other study ID #: CAP 020
• Status: Terminated
• Phase: Phase 4
• Start date: June 14, 2017
• Est. completion date: December 19, 2022

Study information

• Verified date: August 2023
• Source: Centre for the AIDS Programme of Research in South Africa
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Terminated
• Enrollment: 205
• Est. completion date: December 19, 2022
• Est. primary completion date: December 19, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria

• Adults = 18 years of age
• Pulmonary Tuberculosis
• Microbiological confirmation [e.g. GeneXpert Mycobacterium Tuberculosis (MTB) detected and Rifampicin (RIF) resistant and / Line Probe Assay (LPA)] of Multi drug-resistant tuberculosis (MDR-TB) / Pre-Extremely drug-resistant tuberculosis (Pre-XDR-TB) / Extremely drug-resistant tuberculosis (XDR-TB)
• Capacity for providing informed consent
• HIV status - HIV infected and uninfected patients are allowed in the study:
• Patients already on antiretroviral treatment (ART) will be allowed in the study. The antiretroviral treatment regimen will be evaluated for any contraindications to the drugs used.
• HIV infected patients at any CD4 count irrespective of antiretroviral treatment commencement and duration will be included in the study

Exclusion Criteria:

• 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.

Related Conditions & MeSH terms

• Tuberculosis
• Tuberculosis, Multidrug-Resistant

Intervention

Drug:
• Individualized TB treatment with multiple drugs
Patients with drug-resistant TB will receive a combination of any of the following drugs based on whole genome sequencing: rifampicin, rifabutin, isoniazid, high dose isoniazid, pyrazinamide, ethambutol, levofloxacin, moxifloxacin, ofloxacin, gatifloxacin, amikacin, capreomycin, kanamycin, streptomycin, ethionamide, prothionamide, cycloserine, terizidone, pretomanid, linezolid, sutezolid, clofazimine, bedaquiline, delaminid, para-aminosalicylic acid, imipenem/cilastatin, meropenem, amoxicillin/clavulanate, clarithromycin, azithromycin and thioacetazone
• Standardized TB treatment with multiple drugs
Patients with drug-resistant TB with receive a combination of any of the following drugs based on South African Department of Health guidelines: rifampicin, rifabutin, isoniazid, high dose isoniazid, pyrazinamide, ethambutol, levofloxacin, moxifloxacin, ofloxacin, gatifloxacin, amikacin, capreomycin, kanamycin, streptomycin, ethionamide, prothionamide, cycloserine, terizidone, pretomanid, linezolid, sutezolid, clofazimine, bedaquiline, delaminid, para-aminosalicylic acid, imipenem/cilastatin, meropenem, amoxicillin/clavulanate, clarithromycin, azithromycin and thioacetazone

Locations

Country	Name	City	State
South Africa	King Dinuzulu Hospital	Durban	Kwa-Zulu Natal

Sponsors (1)

Lead Sponsor	Collaborator
Centre for the AIDS Programme of Research in South Africa

Country where clinical trial is conducted

South Africa, 

References & Publications (2)

Musser JM. Antimicrobial agent resistance in mycobacteria: molecular genetic insights. Clin Microbiol Rev. 1995 Oct;8(4):496-514. doi: 10.1128/CMR.8.4.496. — View Citation

Outhred AC, Jelfs P, Suliman B, Hill-Cawthorne GA, Crawford AB, Marais BJ, Sintchenko V. Added value of whole-genome sequencing for management of highly drug-resistant TB. J Antimicrob Chemother. 2015 Apr;70(4):1198-202. doi: 10.1093/jac/dku508. Epub 2014 Dec 9. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Culture negative survival rate	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	24 months
Primary	Culture negative survival rate	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	30 months
Secondary	Tuberculosis treatment outcomes	Treatment outcomes are based on treatment success (cure rates and completion of treatment) or mortality or retention in care or time to culture conversion	30 months
Secondary	Rates of adverse events	Rates of adverse events will be compared between arms	30 months
Secondary	Characterization of multi drug-resistant tuberculosis strains	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	30 months
Secondary	Drug Concentration	To determine the drug concentrations and long-term drug exposures to DR-TB drug regimens in DBS and hair samples respectively	30 months
Secondary	Measure of adherence	To compare adherence to DR-TB drugs using drug concentrations in DBS samples, hair samples, pill count data and participant self-report	30 months
Secondary	Evolution of HIV drug resistance	To assess the evolution of HIV drug resistance in patients receiving Bedaquiline and ART for HIV/MDR-TB treatment	30 months
Secondary	Improved assessment and management of DR-TB	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	30 months