Tuberculosis, Multidrug-ResistantPhase 4InDEXNCT03237182
The Individualized M(X) Drug-resistant TB Treatment Strategy Study
A Phase 4 study testing Individualized TB treatment with multiple drugs and Standardized TB treatment with multiple drugs in people with Tuberculosis, Multidrug-Resistant, run by Centre for the AIDS Programme of Research in South Africa at 1 site in South Africa.
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Tuberculosis, Multidrug-Resistant
- What is being tested?
- Individualized TB treatment with multiple drugs and Standardized TB treatment with multiple drugs
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 205 participants
- Where
- 1 siteSouth Africa
- Study dates
- 14 Jun 2017to 19 Dec 2022
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: The Individualized M(X) Drug-resistant TB Treatment Strategy Study A Strategy to Improve Treatment Outcomes in Patients With Drug-resistant TB
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.
Read the 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
- Being tested
- Individualized TB treatment with multiple drugs, Standardized TB treatment with multiple drugs
- Keywords
- whole genome sequencing;
- Medical subject headings
- Tuberculosis, Multidrug-Resistant
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Individualized TB treatment with multiple drugsDrug
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 drugsDrug
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
| Study group | Role | What they receive |
|---|---|---|
| Individualized treatment for drug resistant tuberculosis | Experimental | 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 Receives: Drug: Individualized TB treatment with multiple drugs |
| Standard treatment regimen for drug resistant tuberculosis | Active comparator | As per South African Department of Health Standard of Care for the treatment of drug resistant tuberculosis Receives: Drug: Standardized TB treatment with multiple drugs |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 24 months
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
Measured: 30 months
Secondary outcomes (7)
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
Measured: 30 months
Rates of adverse events
Rates of adverse events will be compared between arms
Measured: 30 months
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
Measured: 30 months
Drug Concentration
To determine the drug concentrations and long-term drug exposures to DR-TB drug regimens in DBS and hair samples respectively
Measured: 30 months
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
Measured: 30 months
Evolution of HIV drug resistance
To assess the evolution of HIV drug resistance in patients receiving Bedaquiline and ART for HIV/MDR-TB treatment
Measured: 30 months
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
Measured: 30 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Aug 2017
- Study start14 Jun 2017
- Primary completion19 Dec 2022
- Study completion19 Dec 2022
Why it stopped: WHO 2022 guidelines for DR-TB treatment are set to change. These guidelines recommend the use of an all-oral short course BPAL regimen.Therefore ongoing implementation of the study is considered futile.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Tuberculosis, Multidrug-ResistantStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- 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)
- Enrolment
- 205 participants (actual)
Sponsor and investigators
- Lead sponsor
- Centre for the AIDS Programme of Research in South Africa
- Sponsor type
- Research network
- Responsible party
- Principal investigator, Dr Nesri Padayatchi, Centre for the AIDS Programme of Research in South Africa
- Investigators
- Nesri Padayatchi, MBChB, PhD, Principal investigator, Centre for the AIDS Programme of Research in South Africa
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03237182
- Sponsor's protocol ID
- CAP 020
- Acronym
- InDEX
- Status last verified
- Aug 2023
- First submitted
- 27 Jul 2017
- Last updated
- 1 Sep 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: Individual participant data that underlie the results of the objectives of the study, after deidentification
Publications
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.
PubMed 8665467Outhred 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.
PubMed 25492392Maseko 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.
PubMed 37653422
Study at a glance
From the registry record, last updated by the sponsor on 1 Sep 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Individualized M(X) Drug-resistant TB Treatment Strategy Study A Strategy to Improve Treatment Outcomes in Patients With Drug-resistant TB
- ClinicalTrials.gov ID
- NCT03237182
- Acronym / sponsor ID
- InDEX / CAP 020
- Conditions
- Tuberculosis, Multidrug-Resistant
- Keywords
- whole genome sequencing;
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: WHO 2022 guidelines for DR-TB treatment are set to change. These guidelines recommend the use of an all-oral short course BPAL regimen.Therefore ongoing implementation of the study is considered futile.
- Enrolment
- 205 participants (actual)
- Lead sponsor
- Centre for the AIDS Programme of Research in South AfricaResearch network
- Study start
- 14 Jun 2017 (actual)
- Primary completion
- 19 Dec 2022 (actual)
- Study completion
- 19 Dec 2022 (actual)
- First posted
- 2 Aug 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- 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
| Arm | Type | Receives |
|---|---|---|
| Individualized treatment for drug resistant tuberculosis | Experimental | Drug: Individualized TB treatment with multiple drugsPatients 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 | Active comparator | Drug: Standardized TB treatment with multiple drugsAs per South African Department of Health Standard of Care for the treatment of drug resistant tuberculosis |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- 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:
Key exclusion criteria (2 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Individualized TB treatment with multiple drugsPatients 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 | Drug | Individualized treatment for drug resistant tuberculosis |
| Standardized TB treatment with multiple drugsPatients 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 | Drug | Standard treatment regimen for drug resistant tuberculosis |
Primary outcome
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
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
7 secondary outcomes
Tuberculosis treatment outcomes
Time frame: 30 months
Rates of adverse events
Time frame: 30 months
Characterization of multi drug-resistant tuberculosis strains
Time frame: 30 months
Drug Concentration
Time frame: 30 months
Measure of adherence
Time frame: 30 months
Evolution of HIV drug resistance
Time frame: 30 months
Improved assessment and management of DR-TB
Time frame: 30 months
Results and safety
The study was stopped early (reason given: WHO 2022 guidelines for DR-TB treatment are set to change. These guidelines recommend the use of an all-oral short course BPAL regimen.Therefore ongoing implementation of the study is considered futile.). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Sep 2023.
- Background: PubMed 8665467Musser 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.
- Background: PubMed 25492392Outhred 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.
- Derived from this study: PubMed 37653422Maseko 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.
- Individual participant dataSharing planned: Yes. Individual participant data that underlie the results of the objectives of the study, after deidentification
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Nesri Padayatchi, MBChB, PhD principal investigator
Centre for the AIDS Programme of Research in South Africa
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Individualized TB treatment with multiple drugs and Standardized TB treatment with multiple drugs in people with Tuberculosis, Multidrug-Resistant, run by Centre for the AIDS Programme of Research in South Africa at 1 site in South Africa.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 1 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in South Africa. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: WHO 2022 guidelines for DR-TB treatment are set to change. These guidelines recommend the use of an all-oral short course BPAL regimen.Therefore ongoing implementation of the study is considered futile.). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Culture negative survival rate (time frame: 24 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03237182, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Sep 2023.