Study to Evaluate Efficacy of LAI When Added to Multi-drug Regimen Compared to Multi-drug Regimen Alone

Study Overview
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Brief Summary
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A study to evaluate the effectiveness of Liposomal Amikacin for Inhalation (LAI) 590 mg administered once daily (QD) when added to multi-drug regimen (MDR) in participants with Nontuberculous Mycobacterial (NTM) lung infection caused by Mycobacterium Avium Complex (MAC) that were refractory to treatment. Participants were randomized 2:1 to LAI 590 mg administered QD + MDR or MDR alone.

Detailed Description
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This is a randomized, open-label, multicenter study of LAI in adult participants with NTM lung infections caused by MAC that were refractory to treatment. Participants received either LAI 590 mg administered QD by inhalation plus a multidrug regimen, hereafter referred to as LAI + MDR or a multidrug regimen alone, hereafter referred to as MDR alone for a minimum of 8 months. Participants who demonstrated culture conversion by Month 6 went on to complete a treatment course of 12 months, starting from the first of 3 negative cultures that defined culture conversion. Sputum culture results were made available to the site after the Month 6 sputum result was known, in time for the Month 8 visit. Prior to the Month 8 visit, the culture results from Baseline to Month 6 inclusively were blinded to the site and Sponsor. The results were blinded to reduce the potential for bias in an open-label study. At Month 8 (-28 to +7 days), after all sputum culture results were made available to the site only, up to and including Month 6, participants were assessed as converters or non-converters. A converter was defined as a participant who had 3 consecutive monthly MAC-negative sputum cultures at any time within the first 6 months of the study. Relapse or recurrence was defined as having MAC-positive sputum cultures in liquid broth media (agar negative) for 3 or more consecutive months, or having at least 1 MAC-positive sputum culture on solid media (agar positive) after achieving culture conversion. A non-converter was defined as a participant who did not have 3 consecutive monthly MAC-negative sputum cultures at any time within the first 6 months of the study. All converters remained in the study. Converters who, after culture conversion, subsequently had MAC-positive sputum cultures in liquid broth media (agar negative) for 1 or 2 consecutive months only by Month 6 also remained in the study. Participants who remained in the study continued their randomized treatment regimen until they completed a total of 12 months of treatment (EOT), starting from the first of 3 negative cultures that defined culture conversion. These participants returned after the EOT visit for 28 days, 3, 6, and 12 months off-treatment follow-up visits. The 12 months off-treatment follow-up visit was the end of study (EOS) visit. No NTM treatment was administered during the off-treatment phase. At Month 8, all non-converters as assessed at the Month 6 visit were discontinued from Study INS-212. Participants who experienced a relapse or recurrence by Month 6 also discontinued from Study INS-212 at their Month 8 visit. These participants were potentially eligible to enter a separate open-label study of LAI (Study INS-312), provided all entry criteria were met for that study.

Official Title
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A Randomized, Open-label, Multicenter Study of Liposomal Amikacin for Inhalation (LAI) in Adult Patients With Nontuberculous Mycobacterial (NTM) Lung Infection Caused by Mycobacterium Avium Complex (MAC) That Are Refractory to Treatment

Conditions
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Mycobacterium Infections, Nontuberculous

Intervention / Treatment
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* Drug: LAI (Liposomal Amikacin for Inhalation) 590 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be continually positive for MAC on sputum culture while adhering to a multi-drug treatment regimen for a minimum duration of 6 months which is either ongoing or was completed no more than 12 months before screening Be diagnosed with MAC NTM lung infection with evidence of nodular bronchiectasis and/or fibrocavitary disease by chest CT Be willing to adhere to multi-drug treatment regimen during the course of the study Exclusion Criteria: Patients with cystic fibrosis Positive pregnancy test or lactation at screening. All women of child bearing potential will be tested. Women not of childbearing potential are defined as postmenopausal (i.e., amenorrheic for at least 1 year), or surgically or naturally sterile. Active pulmonary tuberculosis requiring treatment at screening History of lung transplantation Prior exposure to LAI (including clinical study).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Multi-drug Regimen<br>Participants received their already prescribed anti-mycobacterial regimen (based on the 2007 American Thoracic Society/Infectious Diseases Society of America [ATS/IDSA] Guidelines) | |
| Experimental: LAI + Multi-drug Regimen<br>Participants received LAI 590 mg QD in addition to their already prescribed anti-mycobacterial regimen (based on the 2007 ATS/IDSA Guidelines) LAI 590 mg QD, administered by inhaling drug product that had been aerosolized in an eFlow nebulizer over approximately 14 minutes | Drug: LAI (Liposomal Amikacin for Inhalation) 590 mg<br>* LAI 590 mg QD, administered by inhaling drug product that had been aerosolized in an eFlow nebulizer over approximately 14 minutes.<br>* Other names: ARIKAYCE®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Achieving Culture Conversion by Month 6 in the Liposomal Amikacin for Inhalation (LAI) + Multi-drug Regimen (MDR) Arm Compared to the MDR Alone Arm | Sputum specimens were collected at Screening (Visit 1), Baseline (Visit 2), and at Visits 3 (Month 1) through 8 (Month 6). A negative culture result reflected a negative culture result for all sputum samples collected at each visit. Participants met the primary endpoint of culture conversion by Month 6 if they had 3 consecutive monthly MAC-negative sputum cultures during the first 6 months of the study. A participant needed to achieve the first of 3 consecutive negative sputum cultures (that defined culture conversion) by Month 4 in order to meet the primary endpoint by Month 6. Each participant in the intent to treat (ITT) population (ie, all randomized participants) was classified as either a converter or non-converter by Month 6. | by Month 6 | 
| Number of Participants Achieving Durable Culture Conversion Through 3 Months Off Treatment in the LAI + MDR Arm Compared to the MDR Arm Alone | Sputum specimens were collected at screening, baseline (Day 1), during treatment, and at Months 1, 3, 6, and 12 months off treatment. Culture conversion with durability was defined as achieving culture conversion by Month 6 and then having no more than 2 consecutive broth positive cultures and no Agar positive culture up to 3 months off treatment. Converters with missing broth or Agar sputum culture result after Month 6 up to 3 months off treatment were considered as not achieving culture conversion with durability except those participants who are unable to produce sputum despite reasonable efforts, as reported by source documentation. Participants who had relapse/recurrence, had rescue medication and/or died before reaching 3 months off treatment were considered as not achieving culture conversion with durability. | up to Month 19 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline (Day 1) to Month 6 in the Six-Minute Walk Test (6MWT) Distance in the LAI + MDR Arm Compared to the MDR Alone Arm | A 6-minute walk assessment of exertional capability was performed at Baseline (Day 1) and at Month 6. The standardized protocol based on the ATS guidelines was used. The 6MWT was conducted by a site member who was blinded to the participant's open-label treatment assignment. The analysis of the change from Baseline (Day 1) to Month 6 in the 6MWT distance was performed after the last participant completed Month 6 and his/her 6MWT distance data were available. | at Month 6 | 
| Time to Culture Conversion by Month 6 in the LAI + MDR Arm Compared to the MDR Alone Arm | The time to culture conversion was defined by the date of the first of at least 3 consecutive monthly culture specimens that were Mycobacterium avium complex (MAC)-negative. The 25th percentile time to conversion is the estimated time taken for 25% of participants to convert. The 50th percentile time to conversion is the estimated time taken for 50% of participants to convert. | by Month 6 | 
| Number of Participants Achieving Sustained Culture Conversion at the End of Treatment (EOT) in the LAI + MDR Arm Compared to the MDR Arm Alone | Sustained conversion was evaluated in participants who completed at least 12 months of treatment from the start of culture conversion. Sustained conversion was defined as conversion (3 consecutive negative monthly sputum samples) by Month 6 with no positive agar media culture or no more than 2 broth media cultures up to and including the time point. Participants who did not convert were considered non-sustained conversions. | up to Month 16 | 
| Change in 6-Minute Walk Test (6MWT) Distance at EOT in the LAI Arm Compared to a Multi-drug Regimen Alone | A 6-minute walk assessment of exertional capability was performed at Baseline (Day 1) and up to EOT or Month 16. The standardized protocol based on the ATS guidelines was used. The 6MWT was conducted by a site member who was blinded to the participant's open-label treatment assignment. | up to Month 16 | 
| Change From Baseline (Day 1) at Month 6 in the St. George's Respiratory Questionnaire (SGRQ) Total Score | The SGRQ was completed before administration of study drug at Baseline (Day 1) and Months 3, 6, 8, and 12, and at the EOT visit and the 3 months off treatment visit. The SGRQ is a self-administered questionnaire that has been validated in participants with airways disease, specifically in participants with bronchiectasis. The SGRQ assesses health-related quality of life in participants with chronic pulmonary disease by evaluating 3 health domains: symptoms (distress caused by respiratory symptoms); activity (effects of disturbances on mobility and physical activity); and impacts (the effect of disease on factors such as employment, personal control of one's health, and need for medication). A composite total score is derived as the sum of domain scores for symptoms, activity, and impact (0 = best possible score and 100 = worst possible score). A within patient reduction from baseline in score of 4 units is generally recognized as a clinically meaningful improvement in quality of life. | at Month 6 | 

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