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

NCT02816931 | Completed DMC

• 2 other identifiers: 540-2013-8797D0879701
• Study Type: observational
• Target: 37
• Locations: 1 country
• Sites: 1

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.

Conditions

Tuberculosis, Multidrug Resistant

Keywords

Treatment; Drug Monitoring; Minimum Inhibitory Concentration; Dried Blood Spot Method; Pharmacokinetics; Pharmacodynamics

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (8)

• Sputum culture conversion

  3 months of treatment

• Sputum culture conversion

  2 months of treatment

• Time to sputum culture positivity (TTP)

  3 months

• Change in TB score 2 during the first 3 months of treatment

  3 months

• Changes in drug resistance - WGS (whole genome sequencing) or MIC

  3 months

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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.

You may qualify if:

• Active pulmonary MDR-TB tuberculosis, consenting adult

You may not qualify if:

• 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.

Sponsors & Collaborators

• Karolinska Institutet: lead
• Fudan University: collaborator
• University Medical Center Groningen: collaborator

Study Sites (1)

Xiamen Designated TB hospital

Xiamen, Fujian, China

Location

Related Publications (6)

• 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.

  PMID: 24846578 BACKGROUND

• 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.

  PMID: 25313213 BACKGROUND

• 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.

  PMID: 26989104 BACKGROUND

• 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. No abstract available.

  PMID: 26828056 BACKGROUND

• 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.

  PMID: 33154028 DERIVED

• 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.

  PMID: 30287613 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Mycobacterium tuberculosis isolates will be frozen and stored for whole genome sequencing in order to compare with clinical and phenotypic characteristics. Blood samples will be frozen and stored for drug concentration analysis.

MeSH Terms

Conditions

Tuberculosis, Multidrug-Resistant

Condition Hierarchy (Ancestors)

Tuberculosis; Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Study Officials

• Hu Yi, MD Ass Prof

  Fudan University, Shanghai

  STUDY DIRECTOR

• Sven Hoffner, Prof

  Karolinska Institutet

  STUDY CHAIR

• Biao Xu, Prof

  Fudan University, Shanghai

  STUDY CHAIR

• Thomas Schön, MD Ass Prof

  Kalmar County Hospital

  STUDY CHAIR

• Rongrong Zheng, MD

  Xiamen CDC

  STUDY CHAIR

• Lina Davies Forsman, MD

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

  STUDY CHAIR

• Xiangyang Yao, MD

  Xiamen First Affiliated Hospital

  STUDY CHAIR

• Jan-Willem Alffenaar, Prof PhamD

  University Medical Center of Groningen

  STUDY CHAIR

• Remco Koster, PhamD PhD

  University Medical Center of Groningen

  STUDY CHAIR

• Katarina Niward, MD

  University Hospital, Linkoeping

  STUDY CHAIR

• Judith Bruchfeld, MD Ass. Prof

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

  PRINCIPAL INVESTIGATOR

• Jakob Paues, MD, PhD

  University Hospital, Linkoeping

  STUDY CHAIR

• Johanna Kuhlin, MD, MSc

  Karolinska Institutet

  STUDY CHAIR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Senior Consultant, Associate Professor

Study Record Dates

• First Submitted: April 14, 2016
• First Posted: June 29, 2016
• Study Start: March 1, 2016
• Primary Completion: September 1, 2018
• Study Completion: June 1, 2020
• Last Updated: October 14, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)