Nontuberculous mycobacterial pulmonary disease (NTM-PD)

Primary Objective: To determine the optimal treatment regimen for patients with Mycobacterium abscessus pulmonary disease (MABS-PD). Secondary Objectives: To explore the optimal antibiotic dosing and therapeutic drug monitoring (TDM) strategies. To evaluate the impact of the proposed treatment combinations on health-related quality of life (HRQoL) and their cost-effectiveness. To assess changes in clinical markers such as chest imaging and lung function to predict the onset and treatment response of MABS-PD. To develop biomarkers for predicting the occurrence and treatment response of MABS-PD. To understand MABS infection susceptibility, host immune responses, and treatment responses associated with the progression of MABS-PD. To characterize the genomic features and antibiotic resistance genes of MABS strains isolated from patients in both observational and interventional studies.

Amikacin
Azithromycin
Bedaquiline
Cefoxitin
Clarithromycin
Clofazimine
Doxycycline
Ethambutol
Imipenem/Cilastatin
Linezolid

AMIKACIN SULFATE
AZITHROMYCIN
Bedaquiline
CEFOXITIN SODIUM
CLARITHROMYCIN
CLOFAZIMINE
DOXYCYCLINE
ETHAMBUTOL
cilastatin
imipenem

270
243
240
240
116
121
130
116
110
110
130
131
116
116

500mg
250mg
100mg
1000mg
500mg
100mg
100mg
400mg
500mg
500mg

In the FORMaT trial (Appendix A1 – Intervention Plan), the primary endpoint is the rate of Mycobacterium abscessus (MABS) clearance in respiratory samples among participants who tolerate treatment.

MABS clearance is defined as:
– Four consecutive sputum cultures negative for MABS collected within 4 weeks after completion of the consolidation phase, with at least one sample obtained within this 4-week period; or
– A bronchoalveolar lavage (BAL) sample collected within 4 weeks after completion of the consolidation phase that is negative for MABS culture.

All adverse events (AEs) and serious adverse events (SAEs) occurring during the study will be coded using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and classified as “possible,” “probable,” or “definite” in relation to the study drug and/or its interaction with concomitant medications.

Good tolerability is defined as the absence of AEs or the occurrence of only Grade 1 or Grade 2 AEs per CTCAE.
Poor tolerability is defined as the occurrence of any Grade 3, Grade 4, or Grade 5 AE.

Intervention Group

A positive diagnosis of Mycobacterium abscessus pulmonary disease (MABS-PD) meeting the clinical, radiological, and microbiological criteria of the American Thoracic Society (ATS):
a. Clinical: Presence of pulmonary symptoms, with other possible diagnoses excluded.
b. Radiological:
– Chest X-ray showing nodular or cavitary opacities, or
– High-resolution computed tomography (HRCT) scan showing multifocal bronchiectasis with multiple small nodules.
c. Microbiological:
• Two or more sputum samples collected at different times positive for MABS culture; or
• One positive culture from a bronchial wash or lavage sample; or
• Lung biopsy or other pulmonary tissue showing histopathological features of mycobacterial infection (granulomatous inflammation or acid-fast bacilli [AFB]) and culture positive for nontuberculous mycobacteria (NTM); or
• Tissue showing histopathological evidence of mycobacterial infection (granulomatous inflammation or AFB) and one or more sputum or bronchial wash samples positive for NTM culture.
Screening samples must be collected within the time frame specified in the relevant appendix.

Male or female participants of any age.
(In Taiwan, only participants aged 18 years or older will be enrolled.)

Participants must not have received prior treatment for MABS-PD (including prescribed drugs for other mycobacterial infections or medications with potential MABS activity listed in the FORMaT Restricted Drug List SOP) within 12 months prior to eligibility assessment.

Participant (or parent/legal guardian, if under 18 years of age) must be willing to provide written informed consent.
(In Taiwan, only participants aged 18 years or older may provide consent.)

Investigator judgment: Participant is able to comply with study visits, treatment, and study procedures.

Observational Group

Male or female participants of any age with at least one positive MABS respiratory culture within the 12 months prior to enrollment.

Participant (or parent/legal guardian, if under 18 years of age) must be willing to provide written informed consent.
(In Taiwan, only participants aged 18 years or older will be enrolled.)

Investigator judgment: Participant is able to comply with study visits and study procedures.

Intervention Group

Participants who have received treatment for Mycobacterium abscessus (MABS) within the past 12 months, including medications prescribed for other mycobacterial infections or other agents with known or potential activity against MABS (as listed in the FORMaT Restricted Drug List SOP), except for the use of azithromycin as part of routine therapy for cystic fibrosis or chronic infection–related lung disease.

Positive pregnancy test result during the FORMaT trial in women of childbearing potential.

Female participants who are breastfeeding.

Unwillingness to comply with the acceptable contraception methods described in the protocol.

QTc interval >500 milliseconds, as corrected by the Fridericia method (QTcF).

Known hypersensitivity or allergic reaction to any of the study treatment components without suitable alternatives available, including amikacin, tigecycline, macrolide antibiotics, and clofazimine.

Observational Group

Participants who have received active treatment for MABS within the past 12 months, including medications prescribed for other mycobacterial infections or other agents with potential MABS activity (as listed in the FORMaT Restricted Drug List SOP), except for the use of azithromycin as part of routine therapy for cystic fibrosis or chronic infection–related lung disease.