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

Gram-Positive Bacterial Infections Clinical Trial

Official title:

Drug Exposure and Minimum Inhibitory Concentration in the Treatment of Mycobacterium Avium Complex Lung Disease: a Prospective Observational Cohort Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05824988
• Other study ID #: K22-149Z
• Status: Recruiting
• Start date: April 14, 2023
• Est. completion date: October 2026

Study information

• Verified date: January 2024
• Source: Shanghai Pulmonary Hospital, Shanghai, China
• Contact: Wei Sha, MD, Prof
• Phone: 86 21 65115006
• Email: shfksw[@]126.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: October 2026
• Est. primary completion date: October 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Bacterial Infections
• Communicable Diseases
• Gram-Positive Bacterial Infections
• Infections
• Lung Diseases
• Mycobacterium Avium Complex
• Mycobacterium Avium-Intracellulare Infection
• Mycobacterium Infections

Intervention

Other:
• 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.

Locations

Country	Name	City	State
China	Shanghai Pulmonary Hospital	Shanghai

Sponsors (5)

Lead Sponsor	Collaborator
Shanghai Pulmonary Hospital, Shanghai, China	Fudan University, Karolinska Institutet, Shanghai Municipal Center for Disease Control and Prevention, University of Sydney

Country where clinical trial is conducted

China, 

References & Publications (10)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Proportion of patients with cure of MAC lung disease	The proportion of patients with cure of MAC lung disease at the end of treatment. The definition of treatment outcome will refer to an NTM-NET consensus statement, on the basis of mycobacterial culture as well as patient-reported and/or objective improvement of symptoms.	12-18 months
Secondary	Six-month culture conversion	The proportion of patients with culture negative conversion after 6 months of MAC treatment.	6 months
Secondary	Time to culture conversion	Time (in months) from start of treatment until the first out of three consecutive negative cultures, collected at least 30 days apart.	12-18 months
Secondary	Proportion of patients with significant changes in drug resistance profile	The proportion of patients with significant changes in the drug resistance profile, phenotypic (MIC) and genotypic (whole genome sequencing) of the antimycobacterial drugs used, during MAC treatment.	12-18 months
Secondary	Resolution of pulmonary lesions or cavitation	Resolution or deterioration of pulmonary lesions or cavitation during MAC treatment by CT scan.	12-18 months
Secondary	Proportion of patients with improved forced expiratory volume in 1 second (FEV1)	Decrease or increase of FEV1 during MAC treatment by lung function test.	12-18 months
Secondary	Proportion of patients with improved forced vital capacity (FVC)	Decrease or increase of FVC during MAC treatment by lung function test.	12-18 months
Secondary	Proportion of patients with improved quality of life	Improvement or deterioration of quality of life during MAC treatment by the St. George's Respiratory Questionnaire (SGRQ). The SGRQ score ranges from 0 to 100, with higher scores indicating more limitations.	12-18 months
Secondary	Proportion of patients with grade 3 or 4 adverse events	The proportion of patients with grade 3 or 4 adverse events during MAC treatment, according to the Division of Acquired Immunodeficiency Syndrome (DAIDS) guidelines.	12-18 months
Secondary	Number of patients with recurrence of MAC lung disease	The number of patients with recurrence of MAC lung disease within one year post treatment completion.	24-30 months