| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Adult Subjects with Newly Diagnosed Nontuberculous Mycobacterial
(NTM) Lung Infection Caused by Mycobacterium avium Complex (MAC) |
|
| E.1.1.1 | Medical condition in easily understood language |
Adult Subjects with Newly Diagnosed Nontuberculous Mycobacterial
(NTM) Lung Infection Caused by Mycobacterium avium Complex (MAC) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10061229 |
| E.1.2 | Term | Lung infection |
| E.1.2 | System Organ Class | 100000004862 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To generate evidence demonstrating the domain specification (via modern psychometric methods, [MPMs]), reliability, validity, and responsiveness (within-subject meaningful change) of the patient-reported outcome (PRO) endpoints. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the effect of each treatment arm (amikacin liposome inhalation suspension [ALIS] + background regimen (azithromycin [AZI] + ethambutol [ETH]) and empty liposome control (ELC) + background regimen on the following:
1. Culture conversion by Month 6
2. Patient-reported respiratory symptoms at Month 7
3. Patient-reported fatigue symptoms at Month 7
4. Time to culture conversion
5. Time to first negative culture
6. MAC isolates with amikacin minimum inhibitory concentration (MIC) ≥ 128 μg/mL
7. Recurrence of MAC (relapse)
8. Recurrence of MAC (new infection)
9. Safety and tolerability of ALIS + background regimen |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must satisfy all of the following criteria to be included in the study:
1. Male or female, ≥ 18 years of age (19 years or older in South Korea)
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 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, chronic obstructive pulmonary disease [COPD], bronchiectasis) have been managed according to 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 child-bearing potential [WOCBP] (ie, fertile following menarche and until becoming post-menopausal unless permanently sterile) and fertile men (ie, all men after puberty unless permanently sterile by bilateral orchidectomy) agree to practice 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:
- true abstinence (refraining from heterosexual intercourse during the entire study),
- copper intrauterine device [IUD],
- hormonal methods (levonorgestrel-releasing intrauterine system, progestogen implant, combined oral contraceptive pill [combined with barrier method]),
- exclusive homosexual relationship, or
- sole male partner who has undergone surgical sterilization with confirmation of azoospermia at least 3 months post procedure while participating in the study.
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. |
|
| E.4 | Principal exclusion criteria |
Subjects who meet any of the following criteria will be disqualified from entering the study:
1. Diagnosis of cystic fibrosis (CF)
2. History of more than 3 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 liposomal 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 (eg, 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 use to ALIS, aminoglycosides, or any of their excipients
19. Disseminated MAC infection
20. Positive pregnancy test or lactation at Screening. All WOCBP will be tested. Women not of child-bearing 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 (HIVpositive, 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 times ULN at Screening
25. Absolute neutrophil count ≤ 500/μL at Screening
26. Serum creatinine > 2 times ULN at Screening
27. Current alcohol, medication, or illicit drug abuse
28. Any condition that, in the opinion of the Investigator, interferes with ability to safely complete the study or adhere to study requirements
29. Known and active COVID-19 infection
30. MAC isolate with MIC for clarithromycin ≥ 32 μg/mL at Screening
31. Known hypersensitivity or contraindications to use to ethambutol, azithromycin (including other macrolides or ketolides), or any of their excipients per local labeling guidance |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Findings on psychometric validation optimized and reported for:
1) Cross-sectional validation (modern psychometrics, internal consistency, concurrent validity, and known-groups validity) at Baseline.
2) Test-retest reliability between Screening and Baseline among subjects reporting no change on Patient Global Impression of Severity (PGI-S) between Screening and Baseline. PGI-S anchors will be PRO specific, with a respiratory and fatigue PGI-S applied to the Quality of Life – Bronchiectasis (QOL-B) respiratory domain and Patient-Reported Outcome Measurement Information System – Fatigue-Short Form 7a (PROMIS F-SF 7a), respectively.
3) Within-subject meaningful change estimated via anchor-based methods and validated via empirical cumulative distribution functions (eCDFs) and probability density functions (ePDFs) between Baseline and End of Study (EOS) (Month 7). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) Baseline
2) Between screening and baseline and
3) Between Baseline and End of Study (EOS) (Month 7). |
|
| E.5.2 | Secondary end point(s) |
Proportion of subjects achieving culture conversion by Month 6 (negative cultures for MAC at Month 5 and Month 6)
Change from Baseline to Month 7 in respiratory symptom score
Change from Baseline to Month 7 in fatigue symptom score
Time to culture conversion (first of 2 consecutive negative cultures) of Baseline to EOT assessments)
Time to first negative culture of Baseline to EOT assessments
Proportion of subjects who develop a MAC isolate with amikacin MIC ≥ 128 µg/mL at more than 1 visit at any timepoint during the study
Proportion of subjects who achieved culture conversion and subsequently have at least 1 MAC positive culture in agar media or positive cultures in broth media in at least 2 consecutive visits that is the same species and genome as cultured at Screening/Baseline.
Proportion of subjects who achieved culture conversion and subsequently have at least 1 MAC positive culture in agar media or positive cultures in broth media in at least 2 consecutive visits that is different than cultured at Screening/Baseline (different species or same species but different genome).
Incidence and severity of adverse events (AEs) and treatment-emergent adverse events (TEAEs) and other safety variables (eg, vital signs, physical examination, clinical laboratory values) from Baseline through the end of the study (EOS). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| From Baseline to 1 month off treatment (Month 7). Month 5 and 6 |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| Azithromycin and Ethambutol Tablets |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 85 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Canada |
| Chile |
| Israel |
| Japan |
| Korea, Republic of |
| New Zealand |
| Taiwan |
| United States |
| Austria |
| France |
| Poland |
| Netherlands |
| Spain |
| Greece |
| Belgium |
| Denmark |
| Hungary |
| Portugal |
| Turkey |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 17 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 17 |
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