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

NCT ID: NCT03237182

Last Updated: 2023-09-01

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE4
• Total Enrollment: 205 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-06-14
• Study Completion Date: 2022-12-19

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.

Conditions

Tuberculosis, Multidrug-Resistant

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Individualized treatment for drug resistant tuberculosis

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

Group Type: EXPERIMENTAL

Individualized TB treatment with multiple drugs

Intervention Type: DRUG

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

Standard treatment regimen for drug resistant tuberculosis

As per South African Department of Health Standard of Care for the treatment of drug resistant tuberculosis

Group Type: ACTIVE_COMPARATOR

Standardized TB treatment with multiple drugs

Intervention Type: DRUG

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

Interventions

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

Intervention Type: DRUG

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

Intervention Type: DRUG

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Centre for the AIDS Programme of Research in South Africa

NETWORK

Sponsor Role: lead

Responsible Party

Dr Nesri Padayatchi

Deputy Director

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Nesri Padayatchi, MBChB, PhD

Role: PRINCIPAL_INVESTIGATOR

Centre for the AIDS Programme of Research in South Africa

Locations

King Dinuzulu Hospital

Durban, KwaZulu-Natal, South Africa

Countries

South Africa

References

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.

Reference Type: BACKGROUND

PMID: 8665467 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25492392 (View on PubMed)

Maseko TG, Ngubane S, Letsoalo M, Rambaran S, Archary D, Samsunder N, Perumal R, Chinappa S, Padayatchi N, Naidoo K, Sivro A. Higher plasma interleukin - 6 levels are associated with lung cavitation in drug-resistant tuberculosis. BMC Immunol. 2023 Aug 31;24(1):26. doi: 10.1186/s12865-023-00563-2.

Reference Type: DERIVED

PMID: 37653422 (View on PubMed)

Other Identifiers

CAP 020

Identifier Type: -

Identifier Source: org_study_id