Clinical trial NCT05824988: Drug Exposure and Minimum Inhibitory Concentration in the Treatment of MAC Lung Disease
Official title: Drug Exposure and Minimum Inhibitory Concentration in the Treatment of Mycobacterium Avium Complex Lung Disease: a Prospective Observational Cohort Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Mycobacterium Avium Complex
Mycobacterium Avium-Intracellulare Infection
Gram-Positive Bacterial Infections
Mycobacterium Infections
Keywords: Treatment
Minimum Inhibitory Concentration
Drug Concentration
Pharmacokinetics
Pharmacodynamics
Lead sponsor: Shanghai Pulmonary Hospital, Shanghai, China
Sponsor class: OTHER
Collaborators: name: Fudan University
name: University of Sydney
name: Karolinska Institutet
name: Shanghai Municipal Center for Disease Control and Prevention
First posted: 2023-04-24
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

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

Primary outcomes:
measure: Peak plasma concentration (Cmax) for key antimycobacterial drugs, separate and in relation to minimum inhibitory concentration
timeFrame: one-month of treatment
measure: Area under the plasma concentration versus time curve (AUC) for key antimycobacterial drugs, separate and in relation to minimum inhibitory concentration
timeFrame: one-month of treatment
Secondary outcomes:
measure: Proportion of patients with cure of MAC lung disease
timeFrame: 12-18 months
measure: Six-month culture conversion
timeFrame: 6 months
measure: Time to culture conversion
timeFrame: 12-18 months
measure: Proportion of patients with significant changes in drug resistance profile
timeFrame: 12-18 months
measure: Resolution of pulmonary lesions or cavitation
timeFrame: 12-18 months
measure: Proportion of patients with improved forced expiratory volume in 1 second (FEV1)
timeFrame: 12-18 months
measure: Proportion of patients with improved forced vital capacity (FVC)
timeFrame: 12-18 months
measure: Proportion of patients with improved quality of life
timeFrame: 12-18 months
measure: Proportion of patients with grade 3 or 4 adverse events
timeFrame: 12-18 months
measure: Number of patients with recurrence of MAC lung disease
timeFrame: 24-30 months
Other outcomes:
Locations:
city: Shanghai
country: China
facility: Shanghai Pulmonary Hospital
Study officials:
affiliation: Shanghai Pulmonary Hospital, Shanghai, China
name: Wei Sha, MD, Prof
role: PRINCIPAL_INVESTIGATOR
affiliation: Shanghai Pulmonary Hospital, Shanghai, China
name: Xubin Zheng, MPH, PhD
role: STUDY_DIRECTOR
affiliation: Fudan University
name: Biao Xu, Prof
role: STUDY_CHAIR
affiliation: University of Sydney
name: Jan-Willem Alffenaar, PhamD, Prof
role: STUDY_CHAIR
affiliation: Karolinska Institutet
name: Judith Bruchfeld, Ass. Prof
role: STUDY_CHAIR
affiliation: Fudan University
name: Yi Hu, Ass. Prof
role: STUDY_CHAIR
affiliation: Karolinska Institutet
name: Lina Davies Forsman, MD, PhD
role: STUDY_CHAIR
affiliation: Shanghai Municipal Center for Disease Control and Prevention
name: Yangyi Zhang, MPH
role: STUDY_CHAIR
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