Tuberculosis, Multidrug Resistant Clinical Trial
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.
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.
;
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Completed |
NCT00685360 -
A Trial to Evaluate OPC 67683 in Participants With Pulmonary Sputum Culture-positive, Multidrug-resistant Tuberculosis (TB)
|
Phase 2 | |
| Terminated |
NCT02711735 -
Safety of RUTI® Vaccination in MDR-TB Patients
|
Phase 2 |