Open-label Safety Extension Study Assessing Safety and Tolerability of LAI in Patients Who Participated in Study INS-212

Study Overview
=================
Brief Summary
-----------------
This is an open-label safety extension study to assess the safety and tolerability of once daily dosing of 590 mg Liposomal Amikacin for Inhalation (LAI) added to a multi-drug regimen in participants with nontuberculous mycobacterial (NTM) lung infections due to Mycobacterium avium complex (MAC) who were refractory to therapy and failed to convert in Study INS-212 (NCT02344004).

Detailed Description
-----------------
Safety and tolerability of once daily dosing of 590 mg Liposomal Amikacin for Inhalation (LAI) added to a multi-drug regimen in participants with non-tuberculous mycobacterium (NTM) lung infections due to Mycobacterium avium complex (MAC) who are refractory to therapy and failed to convert in Study INS-212. Participants participating in Study INS-212 who had not achieved the INS-212 protocol definition of culture conversion (3 consecutive monthly negative sputum cultures) or who had experienced a relapse or recurrence (agar positive or more than 2 consecutive broth positive results after culture conversion had occurred) by Month 6, as determined by their sputum culture results from Day 1 through Month 6 and confirmed at their scheduled Month 8 visit, were eligible to participate in Study INS-312. For participants who chose to participate in Study INS-312, the Month 8 visit of Study INS-212 became their end of treatment (EOT) visit; these participants were then asked to provide written informed consent for Study INS-312 and were enrolled directly into Study INS-312 after having met all eligibility criteria. Participants in Study INS-212 had either received 590 mg LAI plus an MDR (LAI + MDR arm) or a multidrug regimen alone (MDR alone arm). All participants in this safety extension study were to continue the multidrug antimycobacterial regimen that they were receiving during Study INS-212 and will receive LAI 590 mg administered daily (QD) for up to 12 months. The participants will remain in the study for up to a total of 13 months (up to 12 months on-treatment plus 1 month off LAI treatment for safety follow up).

Official Title
-----------------
An Open-Label Safety Extension Study to a Multicenter Study of Liposomal Amikacin for Inhalation (LAI) in Adult Patients With Nontuberculous Mycobacterial (NTM) Lung Infections Caused by Mycobacterium Avium Complex (MAC) That Are Refractory to Treatment

Conditions
-----------------
NTM Lung Infection Due to MAC

Intervention / Treatment
-----------------
* Drug: LAI 590 mg
* Drug: Multi-drug regimen


Participation Criteria
=================
Eligibility Criteria
-----------------
Key Inclusion Criteria: had successfully completed the Month 6 and End of Treatment visits in Study INS-212 had not achieved the INS-212 protocol definition of culture conversion by Month 6 in Study INS-212 OR had experienced a relapse or recurrence by Month 6 in Study INS-212. Key Exclusion Criteria: 1. achieved culture conversion without relapse or recurrence in the Study INS-212 study by Month 6

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prior LAI + Multidrug Regimen<br>Participants in the prior Study INS-212 who received LAI+MDR. All participants in this safety extension study received LAI+MDR. | Drug: LAI 590 mg<br>* LAI 590 mg QD: administered by inhaling drug product that had been aerosolized in an investigational eFlow nebulizer over approximately 14 minutes<br>* Other names: ARIKAYCE®;Drug: Multi-drug regimen<br>* Multidrug antimycobacterial regimen from study INS-212<br>|
| Experimental: Prior Multidrug Regimen Alone<br>Participants in the prior Study INS-212 who received MDR alone. All participants in this safety extension study received LAI+MDR. | Drug: LAI 590 mg<br>* LAI 590 mg QD: administered by inhaling drug product that had been aerosolized in an investigational eFlow nebulizer over approximately 14 minutes<br>* Other names: ARIKAYCE®;Drug: Multi-drug regimen<br>* Multidrug antimycobacterial regimen from study INS-212<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | TEAEs are defined as those AEs that occurred on or after the date of first dose of study medication in INS-312 and within 28 days after the last dose. If it couldn't be determined whether the AE is treatment emergent due to a partial onset date, then it was classified as treatment emergent. | From baseline to 28 days after end of treatment, up to 13 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving Culture Conversion by Month 6 and Month 12 | 6 months: Converters are defined as participants who had 3 consecutive monthly MAC-negative sputum cultures by Month 6 (last opportunity to convert was at Month 4). 12 months: Converters are defined as participants who had 3 consecutive monthly MAC-negative sputum cultures by Month 12 (last opportunity to convert was at Month 10). | by Month 6 and Month 12 | 
| Time to Culture Conversion | The time to culture conversion is defined as the date of conversion for participants achieving culture conversion is defined as the date of the first of 3-consecutive monthly negative sputum cultures. Then, the number of days to culture conversion is defined as the difference between the date of conversion and the date of first dose of LAI. | by Month 12 | 
| Change From Baseline (Day 1) to Month 6 and Month 12 in the 6MWT Distance | A 6-minute walk assessment of exertional capability was performed at Baseline (Day 1) and Month 6 and Month 12/EOT. The standardized protocol based on the American Thoracic Society (ATS) guidelines (http://doi.org/10.1164/ajrccm.166.1.at1102) was used. After assessments were performed for heart rate, blood pressure, pulse oximetry (SpO2), dyspnea, and overall fatigue using the Borg scale, participants were instructed to walk on a prescribed course as far as they could in 6 minutes. Pre-test assessment parameters were repeated after exertion. The maximum distance achieved and post exertion heart rate and SpO2 were compared to pre-test values. The maximum distance achieved was recorded in the electronic case report form. | From baseline to Month 12 or end of treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ALIS, ARIKAYCE