Multidrug-resistant TuberculosisPODrtbNCT02727582
Pharmacometric Optimization of Second Line Drugs for MDR Tuberculosis Treatment
An observational study of Multidrug-resistant Tuberculosis, run by University of Cape Town at 2 sites in South Africa.
Trial summary
Multidrug-resistant (MDR) tuberculosis (TB), defined as simultaneous resistance to isoniazid and rifampin, has been declared a global emergency. Treatment outcomes are poor, driven by toxicity and limited efficacy of the 2nd-line anti-TB drugs. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Multidrug-resistant Tuberculosis
- How many people
- 142 participants
- Where
- 2 sitesSouth Africa
- Study dates
- 30 Jul 2015to 30 Jan 2021
- Phase
- Observational
- 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
Study population: 142 Xpert MTB/RIF positive adults (>18 years of age), with or without HIV, and starting the standard 5-drug regimen for MDR-TB. The MDR-TB regimen also applies to patients who have rifampicin mono-resistant TB so these patients will also be eligible for the study.
Who may be able to join
- Age > 18 years Current diagnosis of pulmonary MDR-TB or rifampicin-monoresistant TB
- Baseline sputum sample with positive Gene Xpert MTB/RIF test, or confirmed positive Mycobacterium tuberculosis culture displaying resistance to rifampicin with or without isoniazid resistance on standard DST.
- Eligible for standard MDR-TB treatment regimen (see Table 1), or, started on standard MDR-TB regimen within the past 1 month.
- Written confirmation of informed consent to participate.
- Pregnant women satisfying all other eligibility criteria may be enrolled.
Who cannot join
- Critically ill or medically unstable e.g. organ failure - on ventilator, receiving dialysis for acute renal failure, fulminant hepatitis (can be recruited once stabilized if still eligible), or severe haemoptysis.
- Unwilling to participate, or unable to understand the Participant information and provide full informed consent.
- -
Trial locations and contacts
2 sites in 1 country.
South Africa2 sites
Brooklyn Chest Hospital
Cape Town, Western Cape, 7725
DP Marias Hospital
Cape Town, Western Cape, 7725
About this study
Multidrug-resistant (MDR) tuberculosis (TB), defined as simultaneous resistance to isoniazid and rifampin, has been declared a global emergency. Treatment outcomes are poor, driven by toxicity and limited efficacy of the 2nd-line anti-TB drugs.
Although there is evidence that both anti-TB activity and most of the toxicity of the key drugs are related to drug exposure, the pharmacokinetic/pharmacodynamic (PK/PD) relationships in patients with MDR-TB are poorly characterized. Moreover potential synergy of drug combinations has not been identified in the context of MDR-TB, dosing has not taken into account the concentrations needed to suppress resistance, and the role of minimum inhibitory concentrations (MICs) in dosing is poorly studied.
Read more
There are therefore opportunities to optimize drug doses and combinations to improve efficacy, and reduce toxicity. Based on this observational study of patients on standard treatment for MDR-TB, our proposal builds on novel methodologies we have developed, largely for drug sensitive TB:
- The application of computational analytical techniques to tease out the individual contributions of anti-TB drugs used in combination
- The development of a treatment response biomarker model based on time-to-positivity in liquid culture of serial sputum samples.
- The in vitro determination of PK targets for anti-TB activity and the suppression of resistance using the hollow fiber models of Mycobacterium tuberculosis (Mtb) (HFM-TB).
Thus the research will enhance our understanding of current modalities of TB treatment, while contributing research approaches for future regimen optimization.
This protocol describes the clinical research component (points 1\&2).
Aim 1: To characterize the effects of 2nd-line drug exposures on treatment response in MDR-TB patients. The 2nd-line drugs to be examined are those comprising the standardized regimen used in South Africa: kanamycin, pyrazinamide, moxifloxacin, ethionamide and terizidone.
Hypothesis: Amongst patients on standard MDR-TB treatment, variation in drug exposure has a quantifiable impact on the rates at which viable Mtb are cleared from the sputum.
Aim 2: To identify drug exposures associated with the risk of treatment-related toxicities in patients on a standard 2nd-line regimen for MDR-TB.
Hypothesis: The risks of specific toxicities associated with kanamycin, pyrazinamide, moxifloxacin, ethionamide and terizidone are linked to drug concentrations.
Read the detailed description
Aim 1: To characterize the effects of 2nd-line drug exposures on treatment response in MDR-TB patients. The 2nd-line drugs to be examined are those comprising the standardized regimen used in South Africa: kanamycin, pyrazinamide, moxifloxacin, ethionamide and terizidone.
Hypothesis: Amongst patients on standard MDR-TB treatment, variation in drug exposure has a quantifiable impact on the rates at which viable Mtb are cleared from the sputum.
Rationale: There is substantial variability in the PK parameters of the 2nd-line drugs between patients, and in the susceptibility of individual Mtb isolates to those drugs. Concentration-dependent activity has been demonstrated for moxifloxacin, pyrazinamide and aminoglycosides, and higher doses of moxifloxacin and pyrazinamide have been proposed. Studies are needed to identify the most important determinants of treatment response and to describe the optimal drug exposures in MDR-TB, taking MICs into account. We will describe the exponential decline of viable Mtb in the sputum of MDR-TB patients in a treatment response model based on time-to-positivity in liquid culture, thus furthering the field of TB biomarker research. We will then define the relationship between PK and the rates of eradication of viable Mtb from the sputum of patients on the standard MDR-TB regimen to identify the more potent drugs driving treatment response, and to identify synergism or antagonism between individual drugs. Examples of specific questions that will be addressed include: What is the impact of pyrazinamide resistance on treatment response?; What is the impact of inhA mutations on the effect of ethionamide?; and, Should a higher doses of moxifloxacin and pyrazinamide be considered?
Aim 2: To identify drug exposures associated with the risk of treatment-related toxicities in patients on a standard 2nd-line regimen for MDR-TB.
Hypothesis: The risks of specific toxicities associated with kanamycin, pyrazinamide, moxifloxacin, ethionamide and terizidone are linked to drug concentrations.
Rationale: Treatment limiting adverse drug effects are common in patients on MDR-TB treatment regimens. Although several common toxicities are linked to specific drugs and are thought to be dose-related, the relationship between PK and toxicity has not been adequately studied. Overlapping toxicity of antiretroviral drugs in HIV-infected patients, amongst other risk factors, may be contributory. Minimum drug concentration thresholds associated with increased toxicity would allow optimization of doses by targeting concentrations below which toxicity is common, but above which there is optimal efficacy.
- Conditions
- Multidrug-resistant Tuberculosis
- Keywords
- MDR
- Medical subject headings
- Tuberculosis, Multidrug-Resistant
What is being measured
The primary outcome is the main question the study is designed to answer.
To characterize the effects of 2nd-line drug exposures on treatment response in MDR-TB patients.
To describe the population PK of moxifloxacin, terizidone, ethionamide, pyrazinamide and kanamycin in a cohort of 142 South African patients diagnosed with MDR-TB.
- Develop LC-MS/MS assays to accurately quantify moxifloxacin, terizidone, ethionamide, pyrazinamide and kanamycin in plasma.
- Determine plasma concentrations of the 5 drugs in serial samples (6 samples drawn during a dosing interval) in each patient.
- Develop population nonlinear mixed effects models to describe the plasma PK of the 5 drugs in patients with MDR-TB.
- Estimate individual PK measures of exposure for each drug.
- In those patients who consent to pharmacogenetic evaluation, collect and store a suitable blood sample
Measured: 2 years
Secondary outcomes (1)
To identify drug exposures associated with the risk of treatment-related toxicities in patients on a standard 2nd-line regimen for MDR-TB.
To describe the individual susceptibility and MIC distributions of the infecting strains of Mtb in the study population.
- Determine moxifloxacin, kanamycin, ethionamide, isoniazid, cycloserine and pyrazinamide MICs in baseline culture isolates in each patient and in positive 8-week cultures
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Apr 2016 (estimated)
- Study start30 Jul 2015
- Primary completion30 Jan 2021
- Study completion30 Jan 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Multidrug-resistant TuberculosisStudies 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
- Observational
- Observational model
- Cohort
- Time perspective
- Retrospective
- Enrolment
- 142 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Cape Town
- Sponsor type
- University, hospital or other
- Collaborators
- Baylor Research Institute
- Responsible party
- Principal investigator, Helen Margaret McIlleron, University of Cape Town
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02727582
- Sponsor's protocol ID
- PODrtb
- Acronym
- PODrtb
- Status last verified
- Apr 2021
- First submitted
- 29 Mar 2016
- Last updated
- 29 Apr 2021
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- Yes: The investigators listed on the protocol comprise the study management group and are the custodians of the data generated from the study. All manuscripts arising from the data generated as a result of this study are to be approved by this group before submission for publication. Manuscripts arising from the trial will be submitted to peer-reviewed journals. In accordance with NIH public access policy the final peer-reviewed journal manuscripts will be submitted NIH Manuscript Submission System (NIHMS) upon acceptance for publication, and be made publicly available on PubMed Central no later than 12 months after the official date of publication. All presentations and publications will acknowledge the trial's funding sources. Authorship will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE) and the study management group will resolve any problems of authorship and maintain the quality of publications
Study at a glance
From the registry record, last updated by the sponsor on 29 Apr 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacometric Optimization of Second Line Drugs for MDR Tuberculosis Treatment
- ClinicalTrials.gov ID
- NCT02727582
- Acronym / sponsor ID
- PODrtb / PODrtb
- Conditions
- Multidrug-resistant Tuberculosis
- Keywords
- MDR
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 142 participants (actual)
- Lead sponsor
- University of Cape TownUniversity, hospital or other
- Collaborators
- Baylor Research Institute
- Study start
- 30 Jul 2015 (actual)
- Primary completion
- 30 Jan 2021 (actual)
- Study completion
- 30 Jan 2021 (actual)
- First posted
- 4 Apr 2016 (estimated)
- 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.
Multidrug-resistant (MDR) tuberculosis (TB), defined as simultaneous resistance to isoniazid and rifampin, has been declared a global emergency. Treatment outcomes are poor, driven by toxicity and limited efficacy of the 2nd-line anti-TB drugs.
Although there is evidence that both anti-TB activity and most of the toxicity of the key drugs are related to drug exposure, the pharmacokinetic/pharmacodynamic (PK/PD) relationships in patients with MDR-TB are poorly characterized. Moreover potential synergy of drug combinations has not been identified in the context of MDR-TB, dosing has not taken into account the concentrations needed to suppress resistance, and the role of minimum inhibitory concentrations (MICs) in dosing is poorly studied.
There are therefore opportunities to optimize drug doses and combinations to improve efficacy, and reduce toxicity. Based on this observational study of patients on standard treatment for MDR-TB, our proposal builds on novel methodologies we have developed, largely for drug sensitive TB:
- The application of computational analytical techniques to tease out the individual contributions of anti-TB drugs used in combination
- The development of a treatment response biomarker model based on time-to-positivity in liquid culture of serial sputum samples.
- The in vitro determination of PK targets for anti-TB activity and the suppression of resistance using the hollow fiber models of Mycobacterium tuberculosis (Mtb) (HFM-TB).
Thus the research will enhance our understanding of current modalities of TB treatment, while contributing research approaches for future regimen optimization.
This protocol describes the clinical research component (points 1\&2).
Aim 1: To characterize the effects of 2nd-line drug exposures on treatment response in MDR-TB patients. The 2nd-line drugs to be examined are those comprising the standardized regimen used in South Africa: kanamycin, pyrazinamide, moxifloxacin, ethionamide and terizidone.
Hypothesis: Amongst patients on standard MDR-TB treatment, variation in drug exposure has a quantifiable impact on the rates at which viable Mtb are cleared from the sputum.
Aim 2: To identify drug exposures associated with the risk of treatment-related toxicities in patients on a standard 2nd-line regimen for MDR-TB.
Hypothesis: The risks of specific toxicities associated with kanamycin, pyrazinamide, moxifloxacin, ethionamide and terizidone are linked to drug concentrations.
Detailed description
Aim 1: To characterize the effects of 2nd-line drug exposures on treatment response in MDR-TB patients. The 2nd-line drugs to be examined are those comprising the standardized regimen used in South Africa: kanamycin, pyrazinamide, moxifloxacin, ethionamide and terizidone.
Hypothesis: Amongst patients on standard MDR-TB treatment, variation in drug exposure has a quantifiable impact on the rates at which viable Mtb are cleared from the sputum.
Rationale: There is substantial variability in the PK parameters of the 2nd-line drugs between patients, and in the susceptibility of individual Mtb isolates to those drugs. Concentration-dependent activity has been demonstrated for moxifloxacin, pyrazinamide and aminoglycosides, and higher doses of moxifloxacin and pyrazinamide have been proposed. Studies are needed to identify the most important determinants of treatment response and to describe the optimal drug exposures in MDR-TB, taking MICs into account. We will describe the exponential decline of viable Mtb in the sputum of MDR-TB patients in a treatment response model based on time-to-positivity in liquid culture, thus furthering the field of TB biomarker research. We will then define the relationship between PK and the rates of eradication of viable Mtb from the sputum of patients on the standard MDR-TB regimen to identify the more potent drugs driving treatment response, and to identify synergism or antagonism between individual drugs. Examples of specific questions that will be addressed include: What is the impact of pyrazinamide resistance on treatment response?; What is the impact of inhA mutations on the effect of ethionamide?; and, Should a higher doses of moxifloxacin and pyrazinamide be considered?
Aim 2: To identify drug exposures associated with the risk of treatment-related toxicities in patients on a standard 2nd-line regimen for MDR-TB.
Hypothesis: The risks of specific toxicities associated with kanamycin, pyrazinamide, moxifloxacin, ethionamide and terizidone are linked to drug concentrations.
Rationale: Treatment limiting adverse drug effects are common in patients on MDR-TB treatment regimens. Although several common toxicities are linked to specific drugs and are thought to be dose-related, the relationship between PK and toxicity has not been adequately studied. Overlapping toxicity of antiretroviral drugs in HIV-infected patients, amongst other risk factors, may be contributory. Minimum drug concentration thresholds associated with increased toxicity would allow optimization of doses by targeting concentrations below which toxicity is common, but above which there is optimal efficacy.
Study design
- Observational model
- Cohort
- Time perspective
- Retrospective
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- 142 Xpert MTB/RIF positive adults (>18 years of age), with or without HIV, and starting the standard 5-drug regimen for MDR-TB. The MDR-TB regimen also applies to patients who have rifampicin mono-resistant TB so these patients will also be eligible for the study.
Key inclusion criteria (5 listed)
- Age > 18 years Current diagnosis of pulmonary MDR-TB or rifampicin-monoresistant TB
- Baseline sputum sample with positive Gene Xpert MTB/RIF test, or confirmed positive Mycobacterium tuberculosis culture displaying resistance to rifampicin with or without isoniazid resistance on standard DST.
- Eligible for standard MDR-TB treatment regimen (see Table 1), or, started on standard MDR-TB regimen within the past 1 month.
- Written confirmation of informed consent to participate.
- Pregnant women satisfying all other eligibility criteria may be enrolled.
Key exclusion criteria (3 listed)
- Critically ill or medically unstable e.g. organ failure - on ventilator, receiving dialysis for acute renal failure, fulminant hepatitis (can be recruited once stabilized if still eligible), or severe haemoptysis.
- Unwilling to participate, or unable to understand the Participant information and provide full informed consent.
- -
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
To characterize the effects of 2nd-line drug exposures on treatment response in MDR-TB patients.
Time frame: 2 years
To describe the population PK of moxifloxacin, terizidone, ethionamide, pyrazinamide and kanamycin in a cohort of 142 South African patients diagnosed with MDR-TB. * Develop LC-MS/MS assays to accurately quantify moxifloxacin, terizidone, ethionamide, pyrazinamide and kanamycin in plasma. * Determine plasma concentrations of the 5 drugs in serial samples (6 samples drawn during a dosing interval) in each patient. * Develop population nonlinear mixed effects models to describe the plasma PK of the 5 drugs in patients with MDR-TB. * Estimate individual PK measures of exposure for each drug. * In those patients who consent to pharmacogenetic evaluation, collect and store a suitable blood sample
1 secondary outcome
To identify drug exposures associated with the risk of treatment-related toxicities in patients on a standard 2nd-line regimen for MDR-TB.
Time frame: 2 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Apr 2021.
- Individual participant dataSharing planned: Yes. The investigators listed on the protocol comprise the study management group and are the custodians of the data generated from the study. All manuscripts arising from the data generated as a result of this study are to be approved by this group before submission for publication. Manuscripts arising from the trial will be submitted to peer-reviewed journals. In accordance with NIH public access policy the final peer-reviewed journal manuscripts will be submitted NIH Manuscript Submission System (NIHMS) upon acceptance for publication, and be made publicly available on PubMed Central no later than 12 months after the official date of publication. All presentations and publications will acknowledge the trial's funding sources. Authorship will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE) and the study management group will resolve any problems of authorship and maintain the quality of publications
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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.
The record lists no contact. Use the official record to reach the sponsor.
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Multidrug-resistant Tuberculosis, run by University of Cape Town at 2 sites 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 5 inclusion and 3 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: finished, as of the sponsor's last update on 29 Apr 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites 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.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
To characterize the effects of 2nd-line drug exposures on treatment response in MDR-TB patients. (time frame: 2 years). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 29 Apr 2021.