Drug Exposure and Minimum Inhibitory Concentration in the Treatment of MAC Lung Disease

NCT05824988 | Recruiting

• 1 other identifier: K22-149Z
• Study Type: observational
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

The incidence and prevalence of nontuberculous mycobacteria (NTM) infections have gradually increased over the years worldwide (1-3). In China, Mycobacterium avium complex (MAC) was the most prevalent NTM specie (4), while challenged by long treatment duration, frequent drug-induced adverse events, lack of treatment alternatives, poor treatment outcome and high recurrence rate (5, 6). In order to maximize the efficacy of the few available drugs and prevent the development of drug resistance, ensuring adequate plasma drug concentrations are of importance. Despite the role of pathogen susceptibility, determined by minimum inhibitory concentration (MIC), is non-negligible, the evidences regarding its association with treatment outcome are limited, especially for rifamycin and ethambutol. The difficulties in explaining the clinical values of MIC might partially be attributed to the lack of in vivo drug exposure data, which cannot be accurately predicted by the dose administered because of between-patient pharmacokinetic variability (7). Therapeutic drug monitoring (TDM) is a strategy to guide and personalize treatment by measuring plasma drug concentrations and pathogen susceptibility, which might have the potential to improve treatment response to MAC lung disease. In this observational study, the hypothesis is that the drug exposure and/or MIC of antimycobacterial drugs are correlated to the treatment response of MAC lung disease, which is assessed from the perspective of treatment outcome, mycobacterial culture negative conversion, lung function, radiological presentation and self-reported quality of life. Consenting adult patients with culture-positive MAC lung disease will be recruited in study hospital. Respiratory samples (sputum and/or bronchoalveolar lavage fluid) will be collected regularly for mycobacterial culture on the basis of BACTEC MGIT 960 system and MIC will be determined using a commercial broth microdilution plate. Drug concentrations will be measured at 1 and/or 6 months after treatment initiation using liquid chromatography tandem mass spectrometry (LC-MS/MS). The final treatment outcome is recorded at the end of MAC treatment and defined according to an NTM-NET consensus statement (8).

Conditions

Mycobacterium Avium Complex; Mycobacterium Avium-Intracellulare Infection; Gram-Positive Bacterial Infections; Mycobacterium Infections

Keywords

Treatment; Minimum Inhibitory Concentration; Drug Concentration; Pharmacokinetics; Pharmacodynamics

Outcome Measures

Primary Outcomes (2)

• Peak plasma concentration (Cmax) for key antimycobacterial drugs, separate and in relation to minimum inhibitory concentration

  Descriptive data of the distribution of Cmax for key antimycobacterial drugs in patients with MAC lung disease, with regard to existing recommended levels. Their associations with treatment response will be investigated.

  one-month of treatment

• Area under the plasma concentration versus time curve (AUC) for key antimycobacterial drugs, separate and in relation to minimum inhibitory concentration

  Descriptive data of the distribution of AUC for key antimycobacterial drugs in patients with MAC lung disease, with regard to existing recommended levels. Their associations with treatment response will be investigated.

  one-month of treatment

Secondary Outcomes (10)

• Proportion of patients with cure of MAC lung disease

  12-18 months

• Six-month culture conversion

  6 months

• Time to culture conversion

  12-18 months

• Proportion of patients with significant changes in drug resistance profile

  12-18 months

• Resolution of pulmonary lesions or cavitation

  12-18 months

Study Arms (1)

Patients with MAC lung disease

Other: Drug exposure

Interventions

Drug exposure OTHER

Drug concentrations will be measured after one-month antimycobacterial treatment. Area under drug concentration-time curve (AUC) and maximum concentration (Cmax) will be calculated.

Patients with MAC lung disease

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 diagnosed with and treated for MAC lung disease in study hospital in Shanghai, China will be screened for eligibility. Patients will be informed and asked to participate in the study both orally and in writing.

You may qualify if:

• Culture-positive MAC lung disease
• MAC treatment at the Shanghai Pulmonary Hospital
• A regimen composed of at least the core drugs, i.e., macrolides, rifamycin and ethambutol, in doses not lower than recommended according to the ATS/ERS/ESCMID/IDSA and Chinese national guidelines
• Written informed consent

You may not qualify if:

• Pregnancy
• Confirmed mixed infection with mycobacterial species, including M.tuberculosis and other NTM species
• Ongoing with any antimycobacterial treatment for more than one month, including tuberculosis and NTM
• Patients admitted to the intensive care unit
• Off-label use for any study drugs, such as inhalation of amikacin

Sponsors & Collaborators

• Shanghai Pulmonary Hospital, Shanghai, China: lead
• Fudan University: collaborator
• University of Sydney: collaborator
• Karolinska Institutet: collaborator
• Shanghai Municipal Center for Disease Control and Prevention: collaborator

Study Sites (1)

Shanghai Pulmonary Hospital

Shanghai, 200433, China

RECRUITING

Related Publications (11)

• Winthrop KL, Marras TK, Adjemian J, Zhang H, Wang P, Zhang Q. Incidence and Prevalence of Nontuberculous Mycobacterial Lung Disease in a Large U.S. Managed Care Health Plan, 2008-2015. Ann Am Thorac Soc. 2020 Feb;17(2):178-185. doi: 10.1513/AnnalsATS.201804-236OC.

  PMID: 31830805 BACKGROUND

• Lee H, Myung W, Koh WJ, Moon SM, Jhun BW. Epidemiology of Nontuberculous Mycobacterial Infection, South Korea, 2007-2016. Emerg Infect Dis. 2019 Mar;25(3):569-572. doi: 10.3201/eid2503.181597.

  PMID: 30789139 BACKGROUND

• Ringshausen FC, Wagner D, de Roux A, Diel R, Hohmann D, Hickstein L, Welte T, Rademacher J. Prevalence of Nontuberculous Mycobacterial Pulmonary Disease, Germany, 2009-2014. Emerg Infect Dis. 2016 Jun;22(6):1102-5. doi: 10.3201/eid2206.151642.

  PMID: 27191473 BACKGROUND

• Tan Y, Deng Y, Yan X, Liu F, Tan Y, Wang Q, Bao X, Pan J, Luo X, Yu Y, Cui X, Liao G, Ke C, Xu P, Li X, Zhang C, Yao X, Xu Y, Li T, Su B, Chen Z, Ma R, Jiang Y, Ma X, Bi D, Ma J, Yang H, Li X, Tang L, Yu Y, Wang Y, Song H, Liu H, Wu M, Yang Y, Xue Z, Li L, Li Q, Pang Y. Nontuberculous mycobacterial pulmonary disease and associated risk factors in China: A prospective surveillance study. J Infect. 2021 Jul;83(1):46-53. doi: 10.1016/j.jinf.2021.05.019. Epub 2021 May 25.

  PMID: 34048821 BACKGROUND

• Kwak N, Park J, Kim E, Lee CH, Han SK, Yim JJ. Treatment Outcomes of Mycobacterium avium Complex Lung Disease: A Systematic Review and Meta-analysis. Clin Infect Dis. 2017 Oct 1;65(7):1077-1084. doi: 10.1093/cid/cix517.

  PMID: 28582488 BACKGROUND

• Diel R, Nienhaus A, Ringshausen FC, Richter E, Welte T, Rabe KF, Loddenkemper R. Microbiologic Outcome of Interventions Against Mycobacterium avium Complex Pulmonary Disease: A Systematic Review. Chest. 2018 Apr;153(4):888-921. doi: 10.1016/j.chest.2018.01.024. Epub 2018 Feb 2.

  PMID: 29410162 BACKGROUND

• Magis-Escurra C, Alffenaar JW, Hoefnagels I, Dekhuijzen PN, Boeree MJ, van Ingen J, Aarnoutse RE. Pharmacokinetic studies in patients with nontuberculous mycobacterial lung infections. Int J Antimicrob Agents. 2013 Sep;42(3):256-61. doi: 10.1016/j.ijantimicag.2013.05.007. Epub 2013 Jul 7.

  PMID: 23837923 BACKGROUND

• van Ingen J, Aksamit T, Andrejak C, Bottger EC, Cambau E, Daley CL, Griffith DE, Guglielmetti L, Holland SM, Huitt GA, Koh WJ, Lange C, Leitman P, Marras TK, Morimoto K, Olivier KN, Santin M, Stout JE, Thomson R, Tortoli E, Wallace RJ Jr, Winthrop KL, Wagner D; for NTM-NET. Treatment outcome definitions in nontuberculous mycobacterial pulmonary disease: an NTM-NET consensus statement. Eur Respir J. 2018 Mar 22;51(3):1800170. doi: 10.1183/13993003.00170-2018. Print 2018 Mar. No abstract available.

  PMID: 29567726 BACKGROUND

• Daley CL, Iaccarino JM, Lange C, Cambau E, Wallace RJ Jr, Andrejak C, Bottger EC, Brozek J, Griffith DE, Guglielmetti L, Huitt GA, Knight SL, Leitman P, Marras TK, Olivier KN, Santin M, Stout JE, Tortoli E, van Ingen J, Wagner D, Winthrop KL. Treatment of nontuberculous mycobacterial pulmonary disease: an official ATS/ERS/ESCMID/IDSA clinical practice guideline. Eur Respir J. 2020 Jul 7;56(1):2000535. doi: 10.1183/13993003.00535-2020. Print 2020 Jul.

  PMID: 32636299 BACKGROUND

• Alffenaar JW, Martson AG, Heysell SK, Cho JG, Patanwala A, Burch G, Kim HY, Sturkenboom MGG, Byrne A, Marriott D, Sandaradura I, Tiberi S, Sintchencko V, Srivastava S, Peloquin CA. Therapeutic Drug Monitoring in Non-Tuberculosis Mycobacteria Infections. Clin Pharmacokinet. 2021 Jun;60(6):711-725. doi: 10.1007/s40262-021-01000-6. Epub 2021 Mar 10.

  PMID: 33751415 BACKGROUND

• Zheng X, Wang L, Davies Forsman L, Zhang Y, Chen Y, Luo X, Liu Y, Bruchfeld J, Hu Y, Alffenaar JC, Sha W, Xu B. Correlation of drug exposure and bacterial susceptibility with treatment response for Mycobacterium avium complex lung disease: protocol for a prospective observational cohort study. BMJ Open. 2023 Oct 3;13(10):e075383. doi: 10.1136/bmjopen-2023-075383.

  PMID: 37788924 DERIVED

Biospecimen

Retention: SAMPLES WITH DNA

Mycobacterium avium complex isolates will be frozen and stored for whole genome sequencing in order to explore development of drug resistance-conferring mutations and to distinguish relapse from reinfection. Blood samples will be collected and stored for drug concentration analysis.

MeSH Terms

Conditions

Mycobacterium avium-intracellulare Infection; Gram-Positive Bacterial Infections; Mycobacterium Infections

Condition Hierarchy (Ancestors)

Mycobacterium Infections, Nontuberculous; Actinomycetales Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Study Officials

• Wei Sha, MD, Prof

  Shanghai Pulmonary Hospital, Shanghai, China

  PRINCIPAL INVESTIGATOR

• Xubin Zheng, MPH, PhD

  Shanghai Pulmonary Hospital, Shanghai, China

  STUDY DIRECTOR

• Biao Xu, Prof

  Fudan University

  STUDY CHAIR

• Jan-Willem Alffenaar, PhamD, Prof

  University of Sydney

  STUDY CHAIR

• Judith Bruchfeld, Ass. Prof

  Karolinska Institutet

  STUDY CHAIR

• Yi Hu, Ass. Prof

  Fudan University

  STUDY CHAIR

• Lina Davies Forsman, MD, PhD

  Karolinska Institutet

  STUDY CHAIR

• Yangyi Zhang, MPH

  Shanghai Municipal Center for Disease Control and Prevention

  STUDY CHAIR

Central Study Contacts

Wei Sha, MD, Prof

CONTACT

86 21 65115006; shfksw@126.com

Xubin Zheng, MPH, PhD

CONTACT

86 21 65115006; xbzheng@tongji.edu.cn

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Clinic and Research Center of Tuberculosis, Professor

Study Record Dates

• First Submitted: March 24, 2023
• First Posted: April 24, 2023
• Study Start: April 14, 2023
• Primary Completion: October 1, 2025
• Study Completion (Estimated): October 1, 2026
• Last Updated: January 22, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)