Nontuberculous mycobacterial (NTM) lung infection caused by Mycobacterium avium Complex (MAC) Infections and Infestations Pulmonary mycobacterial infection
Conditions
Interventions
Eligible participants will be randomly assigned to one of the study treatment groups. To try to make sure the same number of participants are in each group, each participant will be randomly assigned
Sponsors
Insmed Switzerland GmbH
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Male or female =18 years of age (19 years or older in South Korea, 20 years or older in Japan) 2. Current diagnosis of MAC lung infection. MAC or mixed infection with MAC as the dominant species is allowed, with MAC as the intended organism for treatment 3. Positive sputum culture for MAC within 6 months prior to Screening 4. Positive sputum culture for MAC at Screening 5. A chest computed tomography (CT) scan read locally, within 6 months prior to Screening to determine the presence and size of pulmonary cavities. Subjects who do not have a chest CT scan within 6 months prior to Screening will be required to obtain a chest CT scan, read locally, during Screening. 6. In the Investigator’s opinion, documented respiratory signs/symptoms at Screening that are attributable to the current MAC lung infection. 7. An average QOL-B Respiratory domain score of =85 based on scores at Screening and on the day of enrollment prior to randomization 8. In the Investigator’s opinion, underlying lung disease (eg. COPD, bronchiectasis) have been managed according to the best local standard of care, and on stable maintenance therapy for a minimum of 4 weeks prior to randomization 9. Willingness and ability to adhere to prescribed study treatment during the study 10. Ability to produce (spontaneously or with induction) approximately 2 ml of sputum for mycobacteriology at Screening 11. Women of childbearing potential (WOCBP) (i.e., fertile following menarche and until becoming postmenopausal unless permanently sterile) and fertile men (i.e., all men after puberty unless permanently sterile by bilateral orchidectomy) agree to practise a highly effective method of birth control from Day 1 to at least 90 days after the last dose. Examples of such birth controls are: 11.1. True abstinence (refraining from heterosexual intercourse during the entire study) 11.2. Copper intrauterine device [IUD] 11.3. Hormonal methods (levonorgestrel-releasing intrauterine system, progestogen implant, combined oral contraceptive pill [combined with barrier method]) 11.4. Exclusive homosexual relationship 11.5. Sole male partner who has undergone surgical sterilization with confirmation of azoospermia at least 3 months post-procedure 12. Provide signed informed consent prior to administration of study drugs or performing any study-related procedure 13. Be able to comply with study drugs use, study visits, and study procedures as defined by the protocol 14. Men with partners who are WOCBP (pregnant or non-pregnant) agree to use condoms and non-pregnant partners should practice a highly effective method of birth control
Exclusion criteria
Exclusion criteria: 1. Diagnosis of CF 2. History of more than three MAC lung infections 3. Received any mycobacterial antibiotic treatment for current MAC lung infection 4. Refractory MAC lung infection, defined as having positive MAC cultures while being treated with a multidrug mycobacterial antibiotic treatment regimen for a minimum of 6 consecutive months and no documented successful treatment, defined as negative sputum culture for MAC and cessation of treatment. 5. Relapse of prior MAC lung infection, defined as positive sputum culture for MAC =6 months of cessation of prior successful treatment 6. MAC isolate with MIC for amikacin =128 µg/ml at screening 7. Evidence of any pulmonary cavity =2 cm in diameter, as determined by chest CT scan, read locally, within 6 months prior to Screening 8. Radiographic finding of new lobar consolidation, atelectasis, significant pleural effusion, or pneumothorax during routine clinical care within 2 months prior to Screening 9. Active pulmonary malignancy (primary or metastatic) or any malignancy requiring chemotherapy or radiation therapy within 1 year prior to Screening or anticipated during the study 10. Active pulmonary tuberculosis requiring treatment during Screening 11. Hospitalization for underlying lung disease during Screening 12. Acute pulmonary exacerbation (e.g., COPD or bronchiectasis) requiring treatment with antibiotics, or corticosteroids (IV or oral), within 4 weeks prior to and during Screening 13. Predicted forced expiratory volume in 1 second (FEV1) < 35%, pre-bronchodilator use. 14. Current smoker 15. History of lung transplantation 16. Use of inhaled or systemic aminoglycosides with activity against MAC (eg, amikacin, kanamycin, or streptomycin) during Screening 17. Prior exposure to ALIS (including clinical study) 18. Known hypersensitivity or contraindications to the use of ALIS, aminoglycosides, or any of their excipients 19. Disseminated MAC infection 20. Positive pregnancy test or lactation at Screening. All women of childbearing potential (WOCBP) will be tested. Women not of childbearing potential are defined as postmenopausal (ie, amenorrheic for 12 months without an alternative medical cause or confirmed by more than one follicle-stimulating hormone [FSH] measurement), or naturally or surgically sterile through bilateral oophorectomy, hysterectomy, or bilateral salpingectomy. For women under the age of 45 years, confirmatory testing with FSH should be considered. 21. Administration of any investigational drug within 8 weeks prior to Screening 22. Known or suspected acquired immunodeficiency syndromes (HIV-positive, regardless of CD4 counts). Other immunodeficiency syndromes that may interfere with study participation in the opinion of the Investigator 23. Significant (as determined by the Investigator) hearing loss, vestibular dysfunction, neuromuscular weakness or a diagnosis of myasthenia gravis, where the potential risk of aminoglycoside toxicity outweighs the potential benefit 24. Aspartate aminotransferase or alanine aminotransferase =3 times the upper limit of normal (ULN) or total bilirubin = 1.5 t
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Respiratory symptoms measured using respiratory symptom score at baseline and month 13 | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Proportion of subjects achieving durable culture conversion at month 15 2. Fatigue symptoms measured using the fatigue symptom score at baseline and month 13 3. Proportion of subjects achieving culture conversion by month 12 (negative cultures for MAC at month 11 and month 12) 4. Proportion of subjects achieving culture conversion by month 6 (negative cultures for MAC at month 5 and month 6) 5. Proportion of subjects achieving culture conversion at any time during treatment (first two consecutive negative cultures) measured at baseline to month 12 6. Time to culture conversion (first of two consecutive negative cultures) measured from baseline to month 12 7. Time to first negative culture measured from baseline to month 12 8. Proportion of subjects who develop a MAC isolate with amikacin minimum inhibitory concentration (MIC) =128 µg/ml at more than one visit at any timepoint during the study, measured from baseline to month 15 9. Proportion of subjects who achieved culture conversion and subsequently have at least one MAC-positive culture in agar media or positive cultures in broth media in at least two consecutive visits that is the same species and genome as that cultured at Screening/Baseline, measured from baseline to month 15 10. Proportion of subjects who achieved culture conversion and subsequently have at least one MAC-positive culture in agar media or positive cultures in broth media in at least two consecutive visits that is different than that cultured at Screening/Baseline (different species or same species but different genome), measured from baseline to month 15 11. Proportion of subjects meeting the within-subject meaningful change threshold as reflected in PRO changes scores computed from baseline in patient-reported symptoms 12. Incidence and severity of adverse events (AE | — |
Countries
Argentina, Australia, Austria, Belgium, Canada, Chile, Denmark, England, France, Greece, Hungary, Israel, Italy, Japan, Netherlands, New Zealand, Poland, Portugal, Scotland, Spain, Taiwan, Turkey, United Kingdom
Outcome results
None listed