Drug Concentrations in the Treatment of MDR-TB Related to Minimum Inhibitory Concentrations (TDM-MDR-TB)

October 12, 2020 updated by: Judith Bruchfeld, Karolinska Institutet

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.

Study Overview

Status

Completed

Conditions

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 Type

Observational

Enrollment (Actual)

37

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
    • Fujian
      • Xiamen, Fujian, China
        • Xiamen Designated TB hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

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.

Description

Inclusion Criteria:

  • Active pulmonary MDR-TB tuberculosis, consenting adult

Exclusion Criteria:

  • 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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
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)
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
after 2 weeks of treatment (rich sampling)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Sputum culture conversion
Time Frame: 3 months of treatment
The proportion of patient's with sputum culture conversion after 3 months of TB treatment
3 months of treatment
Sputum culture conversion
Time Frame: 2 months of treatment
The proportion of patient's with sputum culture conversion after 2 months of TB treatment
2 months of treatment
Time to sputum culture positivity (TTP)
Time Frame: 3 months
Changes in the TTP during the first 3 months of treatment
3 months
Change in TB score 2 during the first 3 months of treatment
Time Frame: 3 months
Decrease or increase of TB score during treatment
3 months
Changes in drug resistance - WGS (whole genome sequencing) or MIC
Time Frame: 3 months
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.
3 months
Time to sputum culture conversion
Time Frame: 24 months
Time (in months) from start of treatment until the first out of two consecutive negative sputum cultures, collected at least 30 days apart.
24 months
Treatment outcome
Time Frame: 36 months
Treatment outcome according to the WHO, including relapse
36 months
EQ-5D Quality of life
Time Frame: 3months
Descriptive analysis of EQ-5D during MDR-TB treatment
3months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Karolinska Institutet

Collaborators

Fudan University
University Medical Center Groningen

Investigators

  • Study Director: Hu Yi, MD Ass Prof, Fudan University, Shanghai
  • Study Chair: Sven Hoffner, Prof, Karolinska Institutet
  • Study Chair: Biao Xu, Prof, Fudan University, Shanghai
  • Study Chair: Thomas Schön, MD Ass Prof, Kalmar County Hospital
  • Study Chair: Rongrong Zheng, MD, Xiamen CDC
  • Study Chair: Lina Davies Forsman, MD, Karolinska Institutet, Department of Medicine, Unit of Infectious Diseases, Stockholm
  • Study Chair: Xiangyang Yao, MD, Xiamen First Affiliated Hospital
  • Study Chair: Jan-Willem Alffenaar, Prof PhamD, University Medical Center of Groningen
  • Study Chair: Remco Koster, PhamD PhD, University Medical Center of Groningen
  • Study Chair: Katarina Niward, MD, University Hospital, Linkoeping
  • Principal Investigator: Judith Bruchfeld, MD Ass. Prof, Karolinska Institutet, Department of Medicine, Unit of Infectious Diseases, Stockholm
  • Study Chair: Jakob Paues, MD, PhD, University Hospital, Linkoeping
  • Study Chair: Johanna Kuhlin, MD, MSc, Karolinska Institutet

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 1, 2016

Primary Completion (Actual)

September 1, 2018

Study Completion (Actual)

June 1, 2020

Study Registration Dates

First Submitted

April 14, 2016

First Submitted That Met QC Criteria

June 24, 2016

First Posted (Estimate)

June 29, 2016

Study Record Updates

Last Update Posted (Actual)

October 14, 2020

Last Update Submitted That Met QC Criteria

October 12, 2020

Last Verified

October 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 540-2013-8797
  • D0879701 (Other Identifier: Swedish Research Council)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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