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

NCT ID: NCT02816931

Last Updated: 2020-10-14

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 37 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2016-03-31
• Study Completion Date: 2020-06-01

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.

Conditions

Tuberculosis, Multidrug Resistant

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Fudan University

OTHER

Sponsor Role: collaborator

University Medical Center Groningen

OTHER

Sponsor Role: collaborator

Karolinska Institutet

OTHER

Sponsor Role: lead

Responsible Party

Judith Bruchfeld

Senior Consultant, Associate Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Hu Yi, MD Ass Prof

Role: STUDY_DIRECTOR

Fudan University, Shanghai

Sven Hoffner, Prof

Role: STUDY_CHAIR

Karolinska Institutet

Biao Xu, Prof

Role: STUDY_CHAIR

Fudan University, Shanghai

Thomas Schön, MD Ass Prof

Role: STUDY_CHAIR

Kalmar County Hospital

Rongrong Zheng, MD

Role: STUDY_CHAIR

Xiamen CDC

Lina Davies Forsman, MD

Role: STUDY_CHAIR

Karolinska Institutet, Department of Medicine, Unit of Infectious Diseases, Stockholm

Xiangyang Yao, MD

Role: STUDY_CHAIR

Xiamen First Affiliated Hospital

Jan-Willem Alffenaar, Prof PhamD

Role: STUDY_CHAIR

University Medical Center of Groningen

Remco Koster, PhamD PhD

Role: STUDY_CHAIR

University Medical Center of Groningen

Katarina Niward, MD

Role: STUDY_CHAIR

University Hospital, Linkoeping

Judith Bruchfeld, MD Ass. Prof

Role: PRINCIPAL_INVESTIGATOR

Karolinska Institutet, Department of Medicine, Unit of Infectious Diseases, Stockholm

Jakob Paues, MD, PhD

Role: STUDY_CHAIR

University Hospital, Linkoeping

Johanna Kuhlin, MD, MSc

Role: STUDY_CHAIR

Karolinska Institutet

Locations

Xiamen Designated TB hospital

Xiamen, Fujian, China

Countries

China

References

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: BACKGROUND

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Reference Type: DERIVED

PMID: 33154028 (View on PubMed)

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.

Reference Type: DERIVED

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Other Identifiers

D0879701

Identifier Type: OTHER

Identifier Source: secondary_id

540-2013-8797

Identifier Type: -

Identifier Source: org_study_id