Clinical trial NCT02816931: Drug Concentrations in the Treatment of MDR-TB Related to Minimum Inhibitory Concentrations
Official title: Plasma Drug Concentrations in the Treatment of Multidrug-resistant Tuberculosis in Relation to Minimum Inhibitory Concentrations - a Prospective Observational Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Tuberculosis, Multidrug Resistant
Keywords: Treatment
Drug Monitoring
Minimum Inhibitory Concentration
Dried Blood Spot Method
Pharmacokinetics
Pharmacodynamics
Lead sponsor: Karolinska Institutet
Sponsor class: OTHER
Collaborators: name: Fudan University
name: University Medical Center Groningen
First posted: 2016-06-29
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

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.

Primary outcomes:
measure: Free area under the curve (fAUC) for second-line TB drugs, separate and in relation to minimum inhibitory concentration (MIC)
timeFrame: after 2 weeks of treatment (rich sampling)
measure: Free maximal concentration (fCmax) for second-line TB drugs, separate and in relation to minimum inhibitory concentration (MIC)
timeFrame: after 2 weeks of treatment (rich sampling)
Secondary outcomes:
measure: Sputum culture conversion
timeFrame: 3 months of treatment
measure: Sputum culture conversion
timeFrame: 2 months of treatment
measure: Time to sputum culture positivity (TTP)
timeFrame: 3 months
measure: Change in TB score 2 during the first 3 months of treatment
timeFrame: 3 months
measure: Changes in drug resistance - WGS (whole genome sequencing) or MIC
timeFrame: 3 months
measure: Time to sputum culture conversion
timeFrame: 24 months
measure: Treatment outcome
timeFrame: 36 months
measure: EQ-5D Quality of life
timeFrame: 3months
Other outcomes:
Locations:
city: Xiamen
country: China
facility: Xiamen Designated TB hospital
state: Fujian
Study officials:
affiliation: Fudan University, Shanghai
name: Hu Yi, MD Ass Prof
role: STUDY_DIRECTOR
affiliation: Karolinska Institutet
name: Sven Hoffner, Prof
role: STUDY_CHAIR
affiliation: Fudan University, Shanghai
name: Biao Xu, Prof
role: STUDY_CHAIR
affiliation: Kalmar County Hospital
name: Thomas Schön, MD Ass Prof
role: STUDY_CHAIR
affiliation: Xiamen CDC
name: Rongrong Zheng, MD
role: STUDY_CHAIR
affiliation: Karolinska Institutet, Department of Medicine, Unit of Infectious Diseases, Stockholm
name: Lina Davies Forsman, MD
role: STUDY_CHAIR
affiliation: Xiamen First Affiliated Hospital
name: Xiangyang Yao, MD
role: STUDY_CHAIR
affiliation: University Medical Center of Groningen
name: Jan-Willem Alffenaar, Prof PhamD
role: STUDY_CHAIR
affiliation: University Medical Center of Groningen
name: Remco Koster, PhamD PhD
role: STUDY_CHAIR
affiliation: University Hospital, Linkoeping
name: Katarina Niward, MD
role: STUDY_CHAIR
affiliation: Karolinska Institutet, Department of Medicine, Unit of Infectious Diseases, Stockholm
name: Judith Bruchfeld, MD Ass. Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: University Hospital, Linkoeping
name: Jakob Paues, MD, PhD
role: STUDY_CHAIR
affiliation: Karolinska Institutet
name: Johanna Kuhlin, MD, MSc
role: STUDY_CHAIR
References:
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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.
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. No abstract available.
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citation: Davies 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.
citation: Davies 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.