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

NCT ID: NCT05824988

Last Updated: 2024-01-22

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 100 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2023-04-14
• Study Completion Date: 2026-10-31

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).

Detailed Description

This is an observational cohort study conducted to enrol consenting adult patients with culture-positive MAC lung disease in study hospital (n=100). The diagnosis and treatment of MAC lung disease will adhere to the ATS/ERS/ESCMID/IDSA and Chinese national guidelines (9, 10). Patients treated with a regimen composed of macrolides, rifamycin and ethambutol at minimum are screened for eligibility. Detailed demographic, behaviour, clinical and laboratory information will be recorded at baseline. Respiratory samples (sputum and/or bronchoalveolar lavage fluid) will be collected at baseline and once every 3 months until treatment completion for mycobacterial culture using BACTEC MGIT 960. Time to mycobacterial culture positivity (TTP) will be recorded to estimate the bacterial load as an alternative for colony forming units count. MIC determination will be performed for baseline, six-month and/or the last available positive culture during treatment with the Sensititre™ SLOMYCO2 Susceptibility Testing Plate, to assess the development of acquired drug resistance.

Drug concentrations will be measured for all study patients at one month after treatment initiation. Rich blood sampling (0, 1, 2, 4, 6 and 8 hours after drug intake) will be implemented for the first 30 patients aged < 65 years to enable the development of population pharmacokinetic models. A limited sampling strategy (2 and 6 hours after drug intake) will be applied for the rest patients to increase the feasibility of study. Additional blood sampling will be given for patients with poor treatment response at six months with limited sampling strategy. The developed pharmacokinetic models will be used to accurately calculate the area under the plasma concentration versus time curve (AUC) and peak plasma concentration (Cmax), as the main exposure variables. To comprehensively assess the response to MAC treatment, mycobacterial culture, lung function test, computerized tomography (CT) scan and questionnaires for well-being will be taken regularly in this study. The final treatment outcome is recorded at the end of MAC treatment and defined according to an NTM-NET consensus statement (8). Post-treatment visits are given at 6 and 12 months after treatment completion to assess the recurrence of MAC lung disease.

Together with bacteria MIC and clinical data, the Cmax/MIC and AUC/MIC for antimycobacterial drugs will be explored to deepen our understandings on the correlation of pharmacokinetic and/or pharmacodynamic indices with treatment response, which may guide development of new dosing strategies.

Conditions

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

Study Design

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

Study Groups

Patients with MAC lung disease

Drug exposure

Intervention Type: 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.

Interventions

Drug exposure

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

Intervention Type: OTHER

Eligibility Criteria

Inclusion Criteria

• 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

Exclusion Criteria

• 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

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

Sponsors

Fudan University

OTHER

Sponsor Role: collaborator

University of Sydney

OTHER

Sponsor Role: collaborator

Karolinska Institutet

OTHER

Sponsor Role: collaborator

Shanghai Municipal Center for Disease Control and Prevention

OTHER

Sponsor Role: collaborator

Shanghai Pulmonary Hospital, Shanghai, China

OTHER

Sponsor Role: lead

Responsible Party

Wei Sha MD & PhD

Director of Clinic and Research Center of Tuberculosis, Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Wei Sha, MD, Prof

Role: PRINCIPAL_INVESTIGATOR

Shanghai Pulmonary Hospital, Shanghai, China

Xubin Zheng, MPH, PhD

Role: STUDY_DIRECTOR

Shanghai Pulmonary Hospital, Shanghai, China

Biao Xu, Prof

Role: STUDY_CHAIR

Fudan University

Jan-Willem Alffenaar, PhamD, Prof

Role: STUDY_CHAIR

University of Sydney

Judith Bruchfeld, Ass. Prof

Role: STUDY_CHAIR

Karolinska Institutet

Yi Hu, Ass. Prof

Role: STUDY_CHAIR

Fudan University

Lina Davies Forsman, MD, PhD

Role: STUDY_CHAIR

Karolinska Institutet

Yangyi Zhang, MPH

Role: STUDY_CHAIR

Shanghai Municipal Center for Disease Control and Prevention

Locations

Shanghai Pulmonary Hospital

Shanghai, , China

Site Status: RECRUITING

Countries

China

Central Contacts

Wei Sha, MD, Prof

Role: CONTACT

shfksw@126.com

86 21 65115006 ext. 2017

Xubin Zheng, MPH, PhD

Role: CONTACT

xbzheng@tongji.edu.cn

86 21 65115006 ext. 3181

Facility Contacts

Xubin Zheng, MPH, PhD

Role: primary

xbzheng@tongji.edu.cn

86 21 65115006 ext. 3181

References

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.

Reference Type: BACKGROUND

PMID: 31830805 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 30789139 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 27191473 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 34048821 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 28582488 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 29410162 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 23837923 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 29567726 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 32636299 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 33751415 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 37788924 (View on PubMed)

Other Identifiers

K22-149Z

Identifier Type: -

Identifier Source: org_study_id