Efficacy and Safety Evaluation of Amikacin Liposome Inhalation Suspension with Azithromycin and Ethambutol in Adult Patients with MAC-Induced NTM Lung Infection
- Trial ID
- 2023-505273-33-00
- Protocol
- INS-416
- Sponsor
- Insmed Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of Amikacin Liposome Inhalation Suspension (ALIS) combined with a background regimen of azithromycin and ethambutol, compared to an empty liposome control (ELC) with the same background regimen, in improving patient-reported respiratory symptoms at Month 13. This is clinically relevant as it aims to assess the potential benefits of ALIS in managing respiratory symptoms in patients with newly diagnosed nontuberculous mycobacterial (NTM) lung infection caused by Mycobacterium avium Complex (MAC), a condition that can significantly impact quality of life.
The secondary objectives include evaluating the efficacy of ALIS plus background regimen compared to ELC plus background regimen on several parameters: - Patient-reported fatigue symptoms at Month 13 - Culture conversion by Month 6, 12, and 13, and at any time during treatment - Time to culture conversion and time to first negative culture - MAC isolates with amikacin minimum inhibitory concentration (MIC) ≥ 128 µg/mL - Recurrence of MAC, distinguishing between relapse and new infection - Within-subject meaningful change threshold estimated in respiratory symptoms from Baseline to Month 13 - Safety and tolerability of ALIS plus background regimen.
Participants
The clinical trial involves a total of **400 participants** diagnosed with **nontuberculous mycobacterial (NTM) lung infection** caused by **Mycobacterium avium complex (MAC)**. The study population includes both male and female subjects aged 18 years and older, with specific age requirements for participants from South Korea and Japan. Participants were selected based on a current diagnosis of MAC lung infection, confirmed by positive sputum cultures and chest CT scans. The trial includes individuals with managed underlying lung diseases such as COPD or bronchiectasis, who are on stable maintenance therapy. Participants are required to adhere to prescribed study treatments and procedures, and women of childbearing potential, as well as fertile men, must agree to use highly effective birth control methods. The trial population is not limited by gender, and it includes vulnerable populations, ensuring a comprehensive evaluation of the treatment's efficacy across diverse demographic groups.
Plans and Procedures
The clinical trial is designed as a **randomized, double-blind, placebo-controlled, active comparator, multicenter study** to evaluate the efficacy and safety of an **Amikacin Liposome Inhalation Suspension (ALIS)**-based regimen in adult subjects with newly diagnosed **nontuberculous mycobacterial (NTM) lung infection** caused by **Mycobacterium avium complex (MAC)**. The trial aims to assess the efficacy of ALIS combined with a background regimen of **azithromycin** and **ethambutol** compared to an empty liposome control with the same background regimen. The primary endpoint is the change in respiratory symptom score from baseline to Month 13. Secondary endpoints include the proportion of subjects achieving culture conversion at various time points and the evaluation of fatigue symptom scores.
The trial is expected to last until June 2026, with participant recruitment having started in October 2020. Participants will be involved in the study for a maximum treatment period of 12 months. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor progress and collect data, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to be adults with a current diagnosis of MAC lung infection, confirmed by positive sputum cultures and a chest CT scan. Participants must also demonstrate the ability to adhere to the study protocol and provide informed consent.
Participants may be withdrawn from the study if they fail to comply with the study protocol, experience adverse events that necessitate discontinuation, or if the investigator deems it in the participant's best interest. The study is conducted under strict ethical guidelines, ensuring the safety and well-being of all participants throughout the trial duration.
Treatment
The clinical trial involves the administration of several **experimental medications** and comparator treatments. The primary experimental medication is **ARIKAYCE liposomal 590 mg nebuliser dispersion**, which contains the active substance **amikacin**. This medication is administered via **inhalation use**. The maximum daily dose is 590 mg, with a total maximum dose of 198,240 mg over a treatment period of up to 12 months. The formulation is a nebuliser dispersion, and participant compliance is monitored through regular assessments.
In addition to the experimental medication, the trial includes a **background regimen** consisting of **azithromycin** and **ethambutol hydrochloride**. Azithromycin is provided in several formulations, including Azithromycin AL 250 mg film-coated tablets, Azitromicina Teva 250 mg film-coated tablets, Azithromycin-ratiopharm 250 mg film-coated tablets, Azithromycin STADA® 250 mg film-coated tablets, and Azithromycin HEXAL 250 mg film-coated tablets. Each formulation is administered orally with a maximum daily dose of 250 mg and a total maximum dose of 84,000 mg over 12 months. The active substance, azithromycin, is of chemical origin, and participant adherence is monitored through pill counts and patient diaries.
Ethambutol hydrochloride is administered as part of the background regimen in two formulations: EMB-Fatol 400 mg film-coated tablets and EMB-Fatol® 100 mg tablets. The route of administration is oral, with a maximum daily dose of 15 mg/kg and a total maximum dose of 638,400 mg/kg over the 12-month treatment period. Compliance is assessed through regular follow-ups and medication logs.
The trial also includes a **placebo** for the Amikacin Liposome for Inhalation Suspension. The placebo is a white translucent suspension composed of dipalmitoylphosphatidylcholine (DPPC) and cholesterol, dispersed in a 1.5% (w/w) sodium chloride solution. It is filled into the same container closure system as the drug product and is used to maintain the double-blind nature of the study. The placebo is administered in the same manner as the experimental medication, and compliance is monitored similarly.
Efficacy
The efficacy of the Amikacin Liposome Inhalation Suspension (ALIS)-based regimen in treating Nontuberculous Mycobacterial (NTM) lung infection caused by Mycobacterium avium Complex (MAC) will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline to Month 13 in the respiratory symptom score, which will be evaluated using patient-reported outcomes. Secondary endpoints include the proportion of subjects achieving durable culture conversion at Month 15, change from baseline to Month 13 in fatigue symptom score, and the proportion of subjects achieving culture conversion by various time points, such as Month 6, Month 12, and Month 13. Additionally, the time to culture conversion and the time to the first negative culture will be measured from baseline to the end of treatment (EOT) assessments.
Other secondary endpoints involve the proportion of subjects who develop a MAC isolate with an amikacin minimum inhibitory concentration (MIC) of ≥ 128 µg/mL at more than one visit during the study, and the proportion of subjects who achieve culture conversion but subsequently have at least one MAC positive culture. The incidence and severity of adverse events (AEs) and treatment-emergent adverse events (TEAEs), along with other safety variables such as vital signs, physical examination, and clinical laboratory values, will also be monitored from baseline through the end of the study (EOS). These efficacy parameters will be collected and analyzed at specified time points throughout the trial to determine the overall effectiveness of the treatment regimen.
Inclusion and Exclusion Criteria
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 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
- 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 (a 4th MAC lung infection is not eligible). 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, during Screening or 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. Forced expiratory volume in 1 second (FEV1) < 35% of predicted, 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.
- 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 of ethambutol, azithromycin (including other macrolides or ketolides), or any of their excipients per local labeling guidance.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 15 Oct 2020 | 12 |
 Belgium | Not Recruiting | 15 Oct 2020 | 23 |
 Denmark | Not Recruiting | 15 Oct 2020 | 23 |
 France | Not Recruiting | 15 Oct 2020 | 90 |
 Germany | Not Recruiting | 15 Oct 2020 | 54 |
 Greece | Not Recruiting | 15 Oct 2020 | 20 |
 Hungary | Not Recruiting | 15 Oct 2020 | 18 |
 Italy | Not Recruiting | 15 Oct 2020 | 79 |
 Poland | Not Recruiting | 15 Oct 2020 | 15 |
 Portugal | Not Recruiting | 15 Oct 2020 | 23 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
EMB-Fatol® 100 mg, Tabletten | Comparator | TABLETTEN | ORAL | 15 | 12 | PRD973454 |
The placebo for Amikacin Liposome for Inhalation Suspension drug product is a white translucent suspension consisting of dipalmitoylphosphatidylcholine
(DPPC) and cholesterol, which are dispersed in 1.5% (w/w) sodium chloride solution. The
placebo is filled into the same container closure system of the drug product | Placebo | N/A | — | — | — | N/A |
Azithromycin-ratiopharm 250mg Filmtabletten | Comparator | FILMTABLETTEN | ORAL USE | 250 | 12 | PRD598079 |
Azithromycin STADA® 250 mg Filmtabletten | Comparator | FILMTABLETTEN | ORAL USE | 250 | 12 | PRD1861387 |
Azithromycin AL 250 mg Filmtabletten | Comparator | FILMTABLETTEN | ORAL USE | 250 | 12 | PRD1861432 |
Azitromicina Teva 250 mg comprimidos recubiertos con película EFG. | Comparator | COMPRIMIDOS RECUBIERTOS CON PELÍCULA | ORAL USE | 250 | 12 | PRD693751 |
EMB-Fatol 400 mg, Filmtabletten | Comparator | FILMTABLETTEN | ORAL USE | 15 | 12 | PRD973456 |
Azithromycin HEXAL 250 mg Filmtabletten | Comparator | FILMTABLETTEN | ORAL USE | 250 | 12 | PRD762974 |
ARIKAYCE liposomal 590 mg nebuliser dispersion | Test | NEBULISER DISPERSION | INHALATION USE | 590 | 12 | PRD8459879 |