| 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 evaluate the efficacy of Amikacin Liposome Inhalation Suspension (ALIS) + background regimen (azithromycin [AZI]) + ethambutol [ETH]) compared to the empty liposome control (ELC) + background regimen on patient reported respiratory symptoms at Month 13 |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of ALIS + background regimen compared to ELC + background regimen on the following:
-Durable culture conversion at Month 15
-Patient reported fatigue symptoms at Month 13
-Culture conversion by Month 12
-Culture conversion by Month 6
-Culture conversion at any time during treatment
-Time to culture conversion
-Time to first negative culture
-MAC isolates with amikacin minimum inhibitory concentration (MIC) ≥ 128 μg/mL
-Recurrence of MAC (relapse)
-Recurrence of MAC (new infection)
-Within-subject meaningful change threshold estimated in respiratory symptoms from Baseline to Month 13
-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, 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 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 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] (ie, fertile following menarche and until becoming postmenopausal 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.
12. Provide signed informed consent prior to administration of any study drug or performing any study related procedure.
13. Be able to comply with study drug 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 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 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 at 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 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 (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) |
| Change from Baseline to Month 13 in respiratory symptom score |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| From baseline to month 13 |
|
| E.5.2 | Secondary end point(s) |
To evaluate the efficacy of ALIS + background regimen compared to ELC + background regimen on the following:
-Proportion of subjects achieving durable culture conversion at Month 15.
-Change from Baseline to Month 13 in fatigue symptom score.
-Proportion of subjects achieving culture conversion by Month 12 (negative cultures for MAC at Month 11 and Month 12).
-Proportion of subjects achieving culture conversion by Month 6 (negative cultures for MAC at Month 5 and Month 6).
-Proportion of subjects achieving culture conversion at any time during treatment (first 2 consecutive negative cultures) of Baseline to EOT assessments.
-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 that 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 that cultured at Screening/Baseline (different species or same species but different genome).
-Proportion of subjects meeting the within-subject meaningful change threshold as reflected in PRO changes scores computed from Baseline in patient-reported symptoms.
-Incidence and severity of adverse events (AEs) and treatmentemergent adverse events (TEAEs) and other safety variables (eg, vital signs, physical examination, clinical laboratory values) from Baseline through the end of study (EOS). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-From baseline to month 13
-Screening
-Months 5, 6, 11, 12, 13 and 15
-EOT |
|
| 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 |
| New Zealand |
| United States |
| Turkey |
| Austria |
| Belgium |
| Denmark |
| France |
| Greece |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Spain |
| Korea, Republic of |
| Taiwan |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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