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Trial record 7 of 9 for:    pretomanid | tb or tuberculosis

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

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ClinicalTrials.gov Identifier: NCT03237182
Recruitment Status : Recruiting
First Posted : August 2, 2017
Last Update Posted : February 24, 2020
Sponsor:
Information provided by (Responsible Party):
Dr Nesri Padayatchi, Centre for the AIDS Programme of Research in South Africa

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.

Condition or disease Intervention/treatment Phase
Tuberculosis, Multidrug-Resistant Drug: Individualized TB treatment with multiple drugs Drug: Standardized TB treatment with multiple drugs Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 448 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Patients randomized to the intervention receive a individualized tuberculosis treatment based on whole genome sequencing and the patients randomized to the control receive the standard of care tuberculosis treatment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: The Individualized M(X) Drug-resistant TB Treatment Strategy Study A Strategy to Improve Treatment Outcomes in Patients With Drug-resistant TB
Actual Study Start Date : June 14, 2017
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Tuberculosis

Arm Intervention/treatment
Experimental: 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
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


Active Comparator: Standard treatment regimen for drug resistant tuberculosis
As per South African Department of Health Standard of Care for the treatment of drug resistant tuberculosis
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





Primary Outcome Measures :
  1. Culture negative survival rate [ Time Frame: 24 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

  2. Culture negative survival rate [ Time Frame: 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 :
  1. Tuberculosis treatment outcomes [ Time Frame: 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

  2. Rates of adverse events [ Time Frame: 30 months ]
    Rates of adverse events will be compared between arms

  3. Characterization of multi drug-resistant tuberculosis strains [ Time Frame: 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

  4. Drug Concentration [ Time Frame: 30 months ]
    To determine the drug concentrations and long-term drug exposures to DR-TB drug regimens in DBS and hair samples respectively

  5. Measure of adherence [ Time Frame: 30 months ]
    To compare adherence to DR-TB drugs using drug concentrations in DBS samples, hair samples, pill count data and participant self-report

  6. Evolution of HIV drug resistance [ Time Frame: 30 months ]
    To assess the evolution of HIV drug resistance in patients receiving Bedaquiline and ART for HIV/MDR-TB treatment

  7. Improved assessment and management of DR-TB [ Time Frame: 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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03237182


Contacts
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Contact: Avika Haridutt, BSc 0731606607 avika.haridutt@caprisa.org
Contact: Resha Boodhram, MMSci 0828383651 resha.boodhram@caprisa.org

Locations
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South Africa
King Dinuzulu Hospital Recruiting
Durban, Kwa-Zulu Natal, South Africa
Contact: Nesri Padayatchi, MBcHB    0312604550    nesri.padayatchi@caprisa.org   
Contact: Avika Haridutt, BSc    0731606607    avika.haridutt@caprisa.org   
Sponsors and Collaborators
Centre for the AIDS Programme of Research in South Africa
Investigators
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Principal Investigator: Nesri Padayatchi, MBChB, PhD Centre for the AIDS Programme of Research in South Africa
Publications:
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Responsible Party: Dr Nesri Padayatchi, Deputy Director, Centre for the AIDS Programme of Research in South Africa
ClinicalTrials.gov Identifier: NCT03237182    
Other Study ID Numbers: CAP 020
First Posted: August 2, 2017    Key Record Dates
Last Update Posted: February 24, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual participant data that underlie the results of the objectives of the study, after deidentification
Supporting Materials: Study Protocol
Time Frame: Beginning 9 months and ending 36 months following article publication
Access Criteria: Investigators wishing to access data from this study will need to contact the PI to request the data. Requests may be submitted up to 36 months following article publication. Investigators will need to complete a proposal for how the data will be used. The proposal will be reviewed by the CAPRISA Scientific Review Committee and the CAPRISA Executive Committee.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Dr Nesri Padayatchi, Centre for the AIDS Programme of Research in South Africa:
whole genome sequencing;
Additional relevant MeSH terms:
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Tuberculosis
Tuberculosis, Multidrug-Resistant
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections