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

Study Overview
=================
Brief 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. 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.

Official Title
-----------------
Plasma Drug Concentrations in the Treatment of Multidrug-resistant Tuberculosis in Relation to Minimum Inhibitory Concentrations - a Prospective Observational Study

Conditions
-----------------
Tuberculosis, Multidrug Resistant

Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------
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) | 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) | 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 | The proportion of patient's with sputum culture conversion after 3 months of TB treatment | 3 months of treatment | 
| Sputum culture conversion | 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) | 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 | Decrease or increase of TB score during treatment | 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. | 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. | 24 months | 
| Treatment outcome | Treatment outcome according to the WHO, including relapse | 36 months | 
| EQ-5D Quality of life | Descriptive analysis of EQ-5D during MDR-TB treatment | 3months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Treatment, Drug Monitoring, Minimum Inhibitory Concentration, Dried Blood Spot Method, Pharmacokinetics, Pharmacodynamics