Tuberculosis, Multidrug ResistantTDM-MDR-TBNCT02816931
Drug Concentrations in the Treatment of MDR-TB Related to Minimum Inhibitory Concentrations
An observational study of Tuberculosis, Multidrug Resistant, run by Karolinska Institutet at 1 site in China.
Trial summary
Multi-drug resistant tuberculosis (MDR-TB) is steadily increasing world-wide, urging for the need of improved treatment strategies. In order to protect the few available drugs that are left, ensuring adequate plasma concentrations of the drugs are important. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Tuberculosis, Multidrug Resistant
- How many people
- 37 participants
- Where
- 1 siteChina
- Study dates
- Mar 2016to 1 Jun 2020
- 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: All adult patients newly diagnosed with pulmonary MDR-TB admitted to the study hospital in Xiamen, China is eligible for inclusion. Phenotypic DST results identifying M. tuberculosis resistant to rifampicin and isoniazid will be performed. Patient's will be informed and asked to participate in the study both orally and in writing.
Who may be able to join
- Active pulmonary MDR-TB tuberculosis, consenting adult
Who cannot join
- HIV, pregnancy, Extensively Drug Resistant TB (XDR-TB), unwilling to participate, critically ill such as admitted to the ICU, ongoing treatment with 5 MDR TB drugs or more for more than 24 hours.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Plasma Drug Concentrations in the Treatment of Multidrug-resistant Tuberculosis in Relation to Minimum Inhibitory Concentrations - a Prospective Observational Study
Multi-drug resistant tuberculosis (MDR-TB) is steadily increasing world-wide, urging for the need of improved treatment strategies. In order to protect the few available drugs that are left, ensuring adequate plasma concentrations of the drugs are important. Individualized therapy using plasma drug concentrations and minimal inhibitory concentration (MIC) determination may be of importance (1). The plasma drug concentrations and the MICs of the second-line drugs will be compared, aiming at increasing the knowledge about pharmacokinetic/pharmacodynamic (PK/PD) indices in the treatment of MDR-TB. In the future, the aim is an individualised therapy, where sub-therapeutic drug concentrations can be adjusted by the use of therapeutic drug monitoring (TDM). TDM in the treatment of MDR-TB may improve clinical outcome for the patients, but plasma concentrations must be assessed together with clinical and microbiological factors (2).
In this observational study the hypothesis is that the ratio between drug concentrations and MICs of the anti-tuberculous drugs, are correlated to the time to sputum culture conversion, the bacterial load measured as time to positive liquid culture (TTP) and clinical outcome. Consenting adult patients with pulmonary MDR-TB patients in China will be recruited. MIC-determination of Mycobacterium tuberculosis will be performed in BACTEC 960 MGIT and drug concentration will be determined at 2, 4 and 8 weeks after treatment initiation using liquid chromatography tandem mass spectrometry (LC-MS/MS), simultaneously assessing Dried Blood Spot (DBS) as a bio-sampling method. Sputum cultures will be obtained regularly throughout the treatment to measure the time to culture positivity (TTP). Clinical follow up according to WHO criteria will be performed at the end of treatment completion.
Read the detailed description
Consenting adult patients with active pulmonary MDR-TB in the study hospital in China (n=50), will be included in the study. Detailed demographic background information as well as baseline clinical characteristics will be collected. Sputum samples for culture and Time to culture positivity (TTP) will be collected at inclusion and at day 2, 7 and week 2, 4, 8 and 12 weeks after start of treatment. MIC-determination of Mycobacterium tuberculosis for all drugs included in the patient's treatment, will be performed mainly using Sensititre TREK kit, complemented with BACTEC 960 MGIT when necessary. After two weeks of TB-treatment, plasma drug concentrations of all the drugs used will be collected. Multiple blood samples (0, 1, 2, 4, 6, 8 and 10 h after drug intake) will be collected in order to accurately calculate the free area under the time-versus concentration curve (fAUC) and maximum concentrations (fCmax). The exposure variables are the fAUC and the fCmax and their ratio with the MIC for the bacteria of the different drugs. Furthermore, blood sampling to assess stability of drug concentrations will be performed at week 8 and week 12 (0, 4 and 6 h post-dose). In order to evaluate if low ratios of fAUC/MIC and fCmax/MIC are associated with poor clinical outcome, clinical parameters as well as sputum culture conversion, time to culture positivity (TTP), inflammatory markers and radiological imaging will be followed up during the first three months of treatment. After treatment completion, the WHO criteria for defining treatment outcome will be applied.
Furthermore, a method of simultaneous determination using LC-MS/MS of the second-line drugs used, will be developed and compared with the use of Dried Blood Spot assay (DBS). DBS has the advantage of enabling drug concentration analysis even in remote areas, since transportation of the filter papers is easy.
- Conditions
- Tuberculosis, Multidrug Resistant
- Keywords
- Treatment, Drug Monitoring, Minimum Inhibitory Concentration, Dried Blood Spot Method, Pharmacokinetics, Pharmacodynamics
- Medical subject headings
- Tuberculosis, Multidrug-Resistant
What is being measured
The primary outcome is the main question the study is designed to answer.
Free area under the curve (fAUC) for second-line TB drugs, separate and in relation to minimum inhibitory concentration (MIC)
Descriptive data of the distribution of fAUC of MDR-TB patients, with regard to existing recommended levels
Measured: after 2 weeks of treatment (rich sampling)
Free maximal concentration (fCmax) for second-line TB drugs, separate and in relation to minimum inhibitory concentration (MIC)
Descriptive data of the distribution of fCmax of MDR-TB patients, with regard to existing recommended levels
Measured: after 2 weeks of treatment (rich sampling)
Secondary outcomes (8)
Sputum culture conversion
The proportion of patient's with sputum culture conversion after 3 months of TB treatment
Measured: 3 months of treatment
Sputum culture conversion
The proportion of patient's with sputum culture conversion after 2 months of TB treatment
Measured: 2 months of treatment
Time to sputum culture positivity (TTP)
Changes in the TTP during the first 3 months of treatment
Measured: 3 months
Change in TB score 2 during the first 3 months of treatment
Decrease or increase of TB score during treatment
Measured: 3 months
Changes in drug resistance - WGS (whole genome sequencing) or MIC
Proportion of patient's with significant changes in the drug resistance, phenotypic (MIC) and genotypic (whole genome sequencing) of the TB drugs used, for patients who are still culture positive after 3 months of treatment.
Measured: 3 months
Time to sputum culture conversion
Time (in months) from start of treatment until the first out of two consecutive negative sputum cultures, collected at least 30 days apart.
Measured: 24 months
Treatment outcome
Treatment outcome according to the WHO, including relapse
Measured: 36 months
EQ-5D Quality of life
Descriptive analysis of EQ-5D during MDR-TB treatment
Measured: 3months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Jun 2016 (estimated)
- Study startMar 2016
- Primary completion1 Sep 2018
- Study completion1 Jun 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Tuberculosis, Multidrug ResistantStudies of the same condition, open and under way.
- More trials run by Karolinska InstitutetThe sponsor's other registered studies.
- 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
- Prospective
- Enrolment
- 37 participants (actual)
Sponsor and investigators
- Lead sponsor
- Karolinska Institutet
- Sponsor type
- University, hospital or other
- Collaborators
- Fudan University, University Medical Center Groningen
- Responsible party
- Principal investigator, Judith Bruchfeld, Karolinska Institutet
- Investigators
- Hu Yi, MD Ass Prof, Study director, Fudan University, ShanghaiSven Hoffner, Prof, Study chair, Karolinska InstitutetBiao Xu, Prof, Study chair, Fudan University, ShanghaiThomas Schön, MD Ass Prof, Study chair, Kalmar County HospitalRongrong Zheng, MD, Study chair, Xiamen CDCLina Davies Forsman, MD, Study chair, Karolinska Institutet, Department of Medicine, Unit of Infectious Diseases, StockholmXiangyang Yao, MD, Study chair, Xiamen First Affiliated HospitalJan-Willem Alffenaar, Prof PhamD, Study chair, University Medical Center of Groningen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02816931
- Sponsor's protocol ID
- 540-2013-8797
- Other IDs
- D0879701
- Acronym
- TDM-MDR-TB
- Status last verified
- Oct 2020
- First submitted
- 14 Apr 2016
- Last updated
- 14 Oct 2020
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
Alsultan A, Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis: an update. Drugs. 2014 Jun;74(8):839-54. doi: 10.1007/s40265-014-0222-8.
PubMed 24846578Chigutsa E, Pasipanodya JG, Visser ME, van Helden PD, Smith PJ, Sirgel FA, Gumbo T, McIlleron H. Impact of nonlinear interactions of pharmacokinetics and MICs on sputum bacillary kill rates as a marker of sterilizing effect in tuberculosis. Antimicrob Agents Chemother. 2015 Jan;59(1):38-45. doi: 10.1128/AAC.03931-14. Epub 2014 Oct 13.
PubMed 25313213Ghimire S, Bolhuis MS, Sturkenboom MG, Akkerman OW, de Lange WC, van der Werf TS, Alffenaar JW. Incorporating therapeutic drug monitoring into the World Health Organization hierarchy of tuberculosis diagnostics. Eur Respir J. 2016 Jun;47(6):1867-9. doi: 10.1183/13993003.00040-2016. Epub 2016 Mar 17. No abstract available.
PubMed 26989104van der Burgt EP, Sturkenboom MG, Bolhuis MS, Akkerman OW, Kosterink JG, de Lange WC, Cobelens FG, van der Werf TS, Alffenaar JW. End TB with precision treatment! Eur Respir J. 2016 Feb;47(2):680-2. doi: 10.1183/13993003.01285-2015. No abstract available.
PubMed 26828056Davies Forsman L, Niward K, Kuhlin J, Zheng X, Zheng R, Ke R, Hong C, Werngren J, Paues J, Simonsson USH, Eliasson E, Hoffner S, Xu B, Alffenaar JW, Schon T, Hu Y, Bruchfeld J. Suboptimal moxifloxacin and levofloxacin drug exposure during treatment of patients with multidrug-resistant tuberculosis: results from a prospective study in China. Eur Respir J. 2021 Mar 11;57(3):2003463. doi: 10.1183/13993003.03463-2020. Print 2021 Mar. No abstract available.
PubMed 33154028Davies Forsman L, Niward K, Hu Y, Zheng R, Zheng X, Ke R, Cai W, Hong C, Li Y, Gao Y, Werngren J, Paues J, Kuhlin J, Simonsson USH, Eliasson E, Alffenaar JW, Mansjo M, Hoffner S, Xu B, Schon T, Bruchfeld J. Plasma concentrations of second-line antituberculosis drugs in relation to minimum inhibitory concentrations in multidrug-resistant tuberculosis patients in China: a study protocol of a prospective observational cohort study. BMJ Open. 2018 Oct 4;8(9):e023899. doi: 10.1136/bmjopen-2018-023899.
PubMed 30287613
Study at a glance
From the registry record, last updated by the sponsor on 14 Oct 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Plasma Drug Concentrations in the Treatment of Multidrug-resistant Tuberculosis in Relation to Minimum Inhibitory Concentrations - a Prospective Observational Study
- ClinicalTrials.gov ID
- NCT02816931
- Acronym / sponsor ID
- TDM-MDR-TB / 540-2013-8797
- Conditions
- Tuberculosis, Multidrug Resistant
- Keywords
- Treatment, Drug Monitoring, Minimum Inhibitory Concentration, Dried Blood Spot Method, Pharmacokinetics, Pharmacodynamics
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 37 participants (actual)
- Lead sponsor
- Karolinska InstitutetUniversity, hospital or other
- Collaborators
- Fudan University, University Medical Center Groningen
- Study start
- Mar 2016 (actual)
- Primary completion
- 1 Sep 2018 (actual)
- Study completion
- 1 Jun 2020 (actual)
- First posted
- 29 Jun 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.
Multi-drug resistant tuberculosis (MDR-TB) is steadily increasing world-wide, urging for the need of improved treatment strategies. In order to protect the few available drugs that are left, ensuring adequate plasma concentrations of the drugs are important. Individualized therapy using plasma drug concentrations and minimal inhibitory concentration (MIC) determination may be of importance (1). The plasma drug concentrations and the MICs of the second-line drugs will be compared, aiming at increasing the knowledge about pharmacokinetic/pharmacodynamic (PK/PD) indices in the treatment of MDR-TB. In the future, the aim is an individualised therapy, where sub-therapeutic drug concentrations can be adjusted by the use of therapeutic drug monitoring (TDM). TDM in the treatment of MDR-TB may improve clinical outcome for the patients, but plasma concentrations must be assessed together with clinical and microbiological factors (2).
In this observational study the hypothesis is that the ratio between drug concentrations and MICs of the anti-tuberculous drugs, are correlated to the time to sputum culture conversion, the bacterial load measured as time to positive liquid culture (TTP) and clinical outcome. Consenting adult patients with pulmonary MDR-TB patients in China will be recruited. MIC-determination of Mycobacterium tuberculosis will be performed in BACTEC 960 MGIT and drug concentration will be determined at 2, 4 and 8 weeks after treatment initiation using liquid chromatography tandem mass spectrometry (LC-MS/MS), simultaneously assessing Dried Blood Spot (DBS) as a bio-sampling method. Sputum cultures will be obtained regularly throughout the treatment to measure the time to culture positivity (TTP). Clinical follow up according to WHO criteria will be performed at the end of treatment completion.
Detailed description
Consenting adult patients with active pulmonary MDR-TB in the study hospital in China (n=50), will be included in the study. Detailed demographic background information as well as baseline clinical characteristics will be collected. Sputum samples for culture and Time to culture positivity (TTP) will be collected at inclusion and at day 2, 7 and week 2, 4, 8 and 12 weeks after start of treatment. MIC-determination of Mycobacterium tuberculosis for all drugs included in the patient's treatment, will be performed mainly using Sensititre TREK kit, complemented with BACTEC 960 MGIT when necessary. After two weeks of TB-treatment, plasma drug concentrations of all the drugs used will be collected. Multiple blood samples (0, 1, 2, 4, 6, 8 and 10 h after drug intake) will be collected in order to accurately calculate the free area under the time-versus concentration curve (fAUC) and maximum concentrations (fCmax). The exposure variables are the fAUC and the fCmax and their ratio with the MIC for the bacteria of the different drugs. Furthermore, blood sampling to assess stability of drug concentrations will be performed at week 8 and week 12 (0, 4 and 6 h post-dose). In order to evaluate if low ratios of fAUC/MIC and fCmax/MIC are associated with poor clinical outcome, clinical parameters as well as sputum culture conversion, time to culture positivity (TTP), inflammatory markers and radiological imaging will be followed up during the first three months of treatment. After treatment completion, the WHO criteria for defining treatment outcome will be applied.
Furthermore, a method of simultaneous determination using LC-MS/MS of the second-line drugs used, will be developed and compared with the use of Dried Blood Spot assay (DBS). DBS has the advantage of enabling drug concentration analysis even in remote areas, since transportation of the filter papers is easy.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- All adult patients newly diagnosed with pulmonary MDR-TB admitted to the study hospital in Xiamen, China is eligible for inclusion. Phenotypic DST results identifying M. tuberculosis resistant to rifampicin and isoniazid will be performed. Patient's will be informed and asked to participate in the study both orally and in writing.
Key inclusion criteria (1 listed)
- Active pulmonary MDR-TB tuberculosis, consenting adult
Key exclusion criteria (1 listed)
- HIV, pregnancy, Extensively Drug Resistant TB (XDR-TB), unwilling to participate, critically ill such as admitted to the ICU, ongoing treatment with 5 MDR TB drugs or more for more than 24 hours.
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
Free area under the curve (fAUC) for second-line TB drugs, separate and in relation to minimum inhibitory concentration (MIC)
Time frame: after 2 weeks of treatment (rich sampling)
Descriptive data of the distribution of fAUC of MDR-TB patients, with regard to existing recommended levels
Free maximal concentration (fCmax) for second-line TB drugs, separate and in relation to minimum inhibitory concentration (MIC)
Time frame: after 2 weeks of treatment (rich sampling)
Descriptive data of the distribution of fCmax of MDR-TB patients, with regard to existing recommended levels
8 secondary outcomes
Sputum culture conversion
Time frame: 3 months of treatment
Sputum culture conversion
Time frame: 2 months of treatment
Time to sputum culture positivity (TTP)
Time frame: 3 months
Change in TB score 2 during the first 3 months of treatment
Time frame: 3 months
Changes in drug resistance - WGS (whole genome sequencing) or MIC
Time frame: 3 months
Time to sputum culture conversion
Time frame: 24 months
Treatment outcome
Time frame: 36 months
EQ-5D Quality of life
Time frame: 3months
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 14 Oct 2020.
- Background: PubMed 24846578Alsultan A, Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis: an update. Drugs. 2014 Jun;74(8):839-54. doi: 10.1007/s40265-014-0222-8.
- Background: PubMed 25313213Chigutsa E, Pasipanodya JG, Visser ME, van Helden PD, Smith PJ, Sirgel FA, Gumbo T, McIlleron H. Impact of nonlinear interactions of pharmacokinetics and MICs on sputum bacillary kill rates as a marker of sterilizing effect in tuberculosis. Antimicrob Agents Chemother. 2015 Jan;59(1):38-45. doi: 10.1128/AAC.03931-14. Epub 2014 Oct 13.
- Background: PubMed 26989104Ghimire S, Bolhuis MS, Sturkenboom MG, Akkerman OW, de Lange WC, van der Werf TS, Alffenaar JW. Incorporating therapeutic drug monitoring into the World Health Organization hierarchy of tuberculosis diagnostics. Eur Respir J. 2016 Jun;47(6):1867-9. doi: 10.1183/13993003.00040-2016. Epub 2016 Mar 17. No abstract available.
- Background: PubMed 26828056van der Burgt EP, Sturkenboom MG, Bolhuis MS, Akkerman OW, Kosterink JG, de Lange WC, Cobelens FG, van der Werf TS, Alffenaar JW. End TB with precision treatment! Eur Respir J. 2016 Feb;47(2):680-2. doi: 10.1183/13993003.01285-2015. No abstract available.
- Derived from this study: PubMed 33154028Davies Forsman L, Niward K, Kuhlin J, Zheng X, Zheng R, Ke R, Hong C, Werngren J, Paues J, Simonsson USH, Eliasson E, Hoffner S, Xu B, Alffenaar JW, Schon T, Hu Y, Bruchfeld J. Suboptimal moxifloxacin and levofloxacin drug exposure during treatment of patients with multidrug-resistant tuberculosis: results from a prospective study in China. Eur Respir J. 2021 Mar 11;57(3):2003463. doi: 10.1183/13993003.03463-2020. Print 2021 Mar. No abstract available.
- Derived from this study: PubMed 30287613Davies Forsman L, Niward K, Hu Y, Zheng R, Zheng X, Ke R, Cai W, Hong C, Li Y, Gao Y, Werngren J, Paues J, Kuhlin J, Simonsson USH, Eliasson E, Alffenaar JW, Mansjo M, Hoffner S, Xu B, Schon T, Bruchfeld J. Plasma concentrations of second-line antituberculosis drugs in relation to minimum inhibitory concentrations in multidrug-resistant tuberculosis patients in China: a study protocol of a prospective observational cohort study. BMJ Open. 2018 Oct 4;8(9):e023899. doi: 10.1136/bmjopen-2018-023899.
- Individual participant dataSharing planned: No
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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.
Hu Yi, MD Ass Prof study director
Fudan University, Shanghai
Sven Hoffner, Prof study chair
Karolinska Institutet
Biao Xu, Prof study chair
Fudan University, Shanghai
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Tuberculosis, Multidrug Resistant, run by Karolinska Institutet at 1 site in China.
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 1 inclusion and 1 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 14 Oct 2020. 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 China. 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?
Free area under the curve (fAUC) for second-line TB drugs, separate and in relation to minimum inhibitory concentration (MIC) (time frame: after 2 weeks of treatment (rich sampling)). 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 NCT02816931, which also lists 6 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 14 Oct 2020.