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

Tuberculosis, Multidrug Resistant Clinical Trial

— TDM-MDR-TB  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02816931
• Other study ID #: 540-2013-8797
• Secondary ID: D0879701
• Status: Completed
• Start date: March 2016
• Est. completion date: June 1, 2020

Study information

• Verified date: October 2020
• Source: Karolinska Institutet
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 37
• Est. completion date: June 1, 2020
• Est. primary completion date: September 1, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Tuberculosis
• Tuberculosis, Multidrug Resistant
• Tuberculosis, Multidrug-Resistant

Locations

Country	Name	City	State
China	Xiamen Designated TB hospital	Xiamen	Fujian

Sponsors (3)

Lead Sponsor	Collaborator
Karolinska Institutet	Fudan University, University Medical Center Groningen

Country where clinical trial is conducted

China, 

References & Publications (4)

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. Review. Erratum in: Drugs. 2014 Jun;74(9):2061. Dosage error in article text. — View Citation

Chigutsa 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. — View Citation

Ghimire 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. — View Citation

van 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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	Sputum culture conversion	The proportion of patient's with sputum culture conversion after 3 months of TB treatment	3 months of treatment
Secondary	Sputum culture conversion	The proportion of patient's with sputum culture conversion after 2 months of TB treatment	2 months of treatment
Secondary	Time to sputum culture positivity (TTP)	Changes in the TTP during the first 3 months of treatment	3 months
Secondary	Change in TB score 2 during the first 3 months of treatment	Decrease or increase of TB score during treatment	3 months
Secondary	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
Secondary	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
Secondary	Treatment outcome	Treatment outcome according to the WHO, including relapse	36 months
Secondary	EQ-5D Quality of life	Descriptive analysis of EQ-5D during MDR-TB treatment	3months