Liposomal Amikacin for Inhalation (LAI) for Nontuberculous Mycobacteria

• Sponsor: Insmed Incorporated (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01315236
• Collaborator: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Enrollment: 90
• Locations: 19
• Arms: 2
• Actual Duration (Months): 37.9
• Patients Per Site: 4.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the efficacy, safety and tolerability of 84 days of daily dosing of 590 mg of LAI versus placebo in patients with treatment refractory NTM lung disease.

The first part of the study is the 84-day double-blind phase to evaluate the primary and secondary endpoints.

Condition or Disease	Intervention/Treatment	Phase
Mycobacterium Infections, Nontuberculous	Drug: Liposomal amikacin for inhalation (LAI); Drug: placebo	Phase 2

Detailed Description

This was a Phase 2, randomized, double-blind study of efficacy, safety, and tolerability of once daily (QD) dosing of LAI 590 mg versus placebo for 84 days in subjects with treatment refractory NTM lung infection on a stable multidrug regimen. At the conclusion of the randomized double-blind phase of the study, subjects who consented to continue in the open-label phase of the study received LAI 590 mg QD for 84 additional days. All subjects were required to complete a 28-day safety follow-up after their end of treatment study visit (Day 168). Subjects completing this study were consented for enrollment in a long-term follow-up phase and were asked to return to the study site at 12 months and 24 months (per protocol Amendment #3, the 24-month follow-up visit was no longer required) (visit window ± 2 months) after the last dose of study drug (either after completing the randomized double-blind phase or the open-label phase). Subjects were stratified upon entering the study based on the presence or absence of cystic fibrosis (CF) and Mycobacterium avium complex versus M abscessus as the predominate NTM organism at baseline and were block randomized to receive either LAI or placebo in a 1:1 ratio in the double-blind phase.

Subjects completing the main study, and subjects who completed the 84-day open-label phase, were consented for enrollment in a post-LAI safety follow-up assessment and were asked to return to the study site 12 months (visit window ± 2 months) after the last dose of study drug (either after completing the randomized double-blind phase or the open-label phase). The screening period required obtaining 3 morning sputum specimens (spontaneous or induced) for mycobacteriology. At each post-screening sputum timepoint, at least 2 and preferably 3 sputum specimens were obtained. At Day 1 (baseline), subjects were evaluated pre-dose and post-dose at the study site. Subjects returned to the study site briefly on Day 2 for collection of serum samples to determine creatinine clearance. On Days 28, 56, and 84, study drug was administered at the site and the efficacy, safety, and tolerability of study drug were evaluated. At Day 85, those subjects continuing in the open-label phase of the study received LAI 590 mg at the study site with pre-dose and post-dose assessments for safety and efficacy. Subjects returned every 28 days (Days 112, 140, and 168) in the open-label phase. A 28-day, post-dose follow-up visit occurred at either Day 112 for those subjects who did not continue in the open-label phase or at Day 196 for those subjects who continued in the open-label phase.

Subjects completing the main study, and subjects who completed the 84-day open-label phase, were consented for enrollment in a post-LAI safety follow-up assessment and were asked to return to the study site 12 months (visit window ± 2 months) after the last dose of study drug (either after completing the randomized double-blind phase or the open-label phase). Arikace™, Arikayce™, Liposomal Amikacin for Inhalation (LAI), and Amikacin Liposome Inhalation Suspension (ALIS) may be used interchangeably throughout this study and other studies evaluating amikacin liposome inhalation suspension.

Study Design

• Study Type: Interventional
• Actual Enrollment: 90 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled Study of Liposomal Amikacin for Inhalation in Patients With Recalcitrant Nontuberculous Mycobacterial Lung Disease
• Actual Study Start Date: Apr 19, 2012
• Actual Primary Completion Date: Aug 18, 2014
• Actual Study Completion Date: Jun 18, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LAI 590 mg QD LAI 590 mg QD	Drug: Liposomal amikacin for inhalation (LAI); Liposomal amikacin for inhalation is provided as a sterile aqueous liposomal dispersion for inhalation via nebulization. 590 mg of liposomal amikacin for inhalation is administered once daily using the PARI Investigational eFlow® Nebulizer. Administration time is approximately 13 minutes. Liposomal amikacin for inhalation will be administered for 84 days in the double-blind, randomized portion of the study. Subjects can continue with 84 additional days of dosing in the open label extension.; Other Names: Amikacin Liposome Inhalation Suspension (ALIS) Arikayce
Placebo Comparator: Placebo placebo QD	Drug: placebo; Placebo is provided as a sterile aqueous lipid dispersion for inhalation via nebulization. Administration procedures, volume and administration time are similar to LAI. Placebo will be administered for 84 days only during the double-blind, randomized portion of the study.

Outcome Measures

Primary Outcome Measures

1. Change in Semi-Quantitative Mycobacterial Culture Results From Baseline to Day 84. [Baseline and end of double-blind phase of 84 days]

   The endpoint used the 7-step semi-quantitative scale (SQS) for mycobacterial culture reporting in both solid and liquid growth media, with step 1 = culture negative in both solid and liquid media, step 2 = growth in liquid medium only, 3 = solid medium positive, 4 = 50 to 100 colonies in solid medium & growth in liquid, 5 = >100 to 200 colonies in solid medium & growth in liquid, 6 = >200 to 500 colonies in solid medium & growth in liquid, 7 = >500 colonies in solid medium & growth in liquid. Full scale range is 1 (best score) to 7 (worst score). The change in step measures the growth at Day 84 compared to the growth at Baseline. The negative values represent reduction in colony growth.

Secondary Outcome Measures

1. Number of Subjects With Negative NTM Culture for the LAI Arm at Day 84 Compared to the Placebo Arm at Day 84 [84 days double-blind phase]

   Sputum specimens were cultured in liquid media in addition to solid media (agar). If results were negative on agar, the liquid media was held for 6 weeks before reporting as culture negative. Culture was negative when confirmed with no growth in liquid medium.

2. Time to Negative NTM Culture….During the 84-day Double-blind Treatment Phase [84 days double-blind phase]

   Sputum specimens were cultured in liquid media in addition to solid media (agar). If results were negative on agar, the liquid media was held for 6 weeks before reporting as culture negative. Culture was negative when confirmed with no growth in liquid medium.

3. Ordinal, 3-level Response From Baseline on the SQS for Mycobacterial Culture for the LAI Arm at Day 84 Compared to the Placebo Arm at Day 84 [Baseline and end of double-blind phase of 84 days]

   The ordinal, 3-level response are (1) improvement (2) no change (3) worsening or death

4. Change From Baseline in Respiratory and Systemic Symptoms Questionnaire (RSSQ) Score at Day 84 for the LAI Arm Compared to the Placebo Arm [Baseline to day 84.]

   The RSSQ was administered to gather information from the subject about the types of symptoms that the subject has experienced since the last contact. A reduction in score indicates improvement. The range of values for the scores are -2 (best) to +2 (worst) in whole numbers. The composite score was calculated by averaging the scores of the subscales.

5. Change From Baseline in Global Rating of Health (GRH) at Day 84 for the LAI Arm Compared to the Placebo Arm [Baseline and end of double-blind phase of 84 days]

   The assessing physician asked the subject to rate his/her assessment of health according to the GRH. Subject responses to, "How would you rate your health at the present time?" included: Excellent, Good, Fair, or Poor.

6. Number of Participants Requiring "Rescue" Anti-mycobacterial or Other "Rescue" Drugs During the 84-day Double-blind Phase [84 days double-blind phase]

   Per the study protocol, study subjects were on a stable, multi-drug, anti-mycobacterial regimen based on the 2007 ATS/IDSA Guidelines; the regimen should not have changed during the study period except for safety concerns. The need for changes to the concurrent anti-mycobacterial regimen or "rescue" therapy was at the discretion of the Investigator and was tracked as a study outcome.

7. Number of Subject for "Rescue" Anti-mycobacterial or Other "Rescue" Drugs During the 84-day Double-blind Phase [84 days double-blind phase]

   Per the study protocol, study subjects were on a stable, multi-drug, anti-mycobacterial regimen based on the 2007 ATS/IDSA Guidelines; the regimen should not have changed during the study period except for safety concerns. The need for changes to the concurrent anti-mycobacterial regimen or "rescue" therapy was at the discretion of the Investigator and was tracked as a study outcome.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 85 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

1. Diagnosis of pulmonary nontuberculous mycobacterial lung disease in accordance with the 2007 ATS/IDSA criteria with evidence of nodular bronchiectasis and/or cavitary disease by chest computed tomography (CT).

2. History of chronic infection with either Mycobacterium avium complex or Mycobacterium abscessus or mixed infection with both species (defined as at least 2 documented positive cultures in the prior 2 years, of which at least one was obtained in the 6 months prior to screening).

3. Positive sputum culture obtained at screening visit with either Mycobacterium avium complex or Mycobacterium abscessus or mixed infection with one dominant species.

4. Receiving ATS/IDSA guidelines-based treatment regimen defined as: adherent to a multi-drug regimen for at least 6 months prior to screening with persistently positive mycobacterial cultures.

5. Ability to produce at least 3 mL of sputum or be willing to undergo an induction that produces at least 3 mL of sputum for clinical evaluation.

6. Female of childbearing potential agrees to practice an acceptable method of birth control (e.g., abstinence, hormonal or barrier methods, partner sterilization, or IUD).

Key Exclusion Criteria:

1. Forced Expiratory Volume in 1 second (FEV1) <30% of predicted at Screening.

2. Presence of any clinically significant cardiac disease as determined by Investigator. The QTc criteria for Exclusion is QTc> 450 msec for males or QTc> 470 msec for females.

3. Subjects with hemoptysis of ≥60 mL in a 24 hour period within 4 weeks prior to screening.

4. Active pulmonary malignancy (primary or metastatic) or any malignancy requiring chemotherapy or radiation therapy within one year prior to screening or anticipated during the study period.

5. Active allergic bronchopulmonary mycosis or any other condition requiring systemic steroids at a dose > equivalent of 10 mg/day of prednisone within 3 months prior to screening or anticipated during the study period.

6. Pulmonary tuberculosis requiring treatment or treated within 2 years prior to screening.

7. History of lung transplantation.

8. Hypersensitivity to aminoglycosides.

9. Any change in chronic NTM multi-drug regimen within 28 days prior to Study Day 1.

10. Evidence of biliary cirrhosis with portal hypertension.

11. History of daily, continuous oxygen supplementation.

12. Smoking tobacco or any substance within 6 months prior to screening or anticipated inability to refrain from smoking throughout the study.

Subjects with CF or primary ciliary dyskinesia were eligible to participate in the study if all eligibility criteria defined above were met. Subjects with CF were required to have documented confirmation of CF to be eligible for the study. The CF diagnosis had to be documented by a positive sweat test ≥ 60 mmol/L or by DNA analysis revealing both mutated alleles consistent with CF disease.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Birmingham	Alabama	United States
2		Stanford	California	United States
3		Denver	Colorado	United States
4		Washington	District of Columbia	United States
5		Gainesville	Florida	United States
6		Miami	Florida	United States
7		Tampa	Florida	United States
8		Kansas City	Kansas	United States
9		Bethesda	Maryland	United States
10		Rochester	Minnesota	United States
11		New York	New York	United States
12		Chapel Hill	North Carolina	United States
13		Cleveland	Ohio	United States
14		Portland	Oregon	United States
15		Philadelphia	Pennsylvania	United States
16		Charleston	South Carolina	United States
17		Tyler	Texas	United States
18		Milwaukee	Wisconsin	United States
19		Hamilton	Ontario	Canada

Sponsors and Collaborators

• Insmed Incorporated
• National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Study Director: Gina Eagle, Insmed Incorporated

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Insmed Incorporated
• ClinicalTrials.gov Identifier: NCT01315236
• Other Study ID Numbers: TR02-112
• First Posted: Mar 15, 2011
• Last Update Posted: Aug 21, 2019
• Last Verified: Aug 1, 2019

• Keywords provided by Insmed Incorporated: Amikacin Liposome Inhalation Suspension (ALIS); Arikayce
• Additional relevant MeSH terms: Mycobacterium Infections; Mycobacterium Infections, Nontuberculous; Respiratory Aspiration; Amikacin

Study Results

Participant Flow

Recruitment Details	One patient out of the 90 was randomized but not dosed.

Arm/Group Title	LAI 590 mg QD	Placebo
Arm/Group Description	LAI 590 mg QD Liposomal amikacin for inhalation (LAI): - Liposomal amikacin for inhalation is provided as a sterile aqueous liposomal dispersion for inhalation via nebulization. 590 mg of liposomal amikacin for inhalation is administered once daily using the PARI Investigational eFlow® Nebulizer. Administration time is approximately 13 minutes. Liposomal amikacin for inhalation will be administered for 84 days in the double-blind, randomized portion of the study. Subjects can continue with 84 additional days of dosing in the open label extension.	placebo QD placebo: - Placebo is provided as a sterile aqueous lipid dispersion for inhalation via nebulization. Administration procedures, volume and administration time are similar to LAI. Placebo will be administered for 84 days only during the double-blind, randomized portion of the study.
Period Title: Double-blind Phase
STARTED	44	45
COMPLETED	40	45
NOT COMPLETED	4	0
Period Title: Double-blind Phase
STARTED	35	43
COMPLETED	34	41
NOT COMPLETED	1	2
Period Title: Double-blind Phase
STARTED	27	32
COMPLETED	26	31
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	LAI 590 mg QD	Placebo	Total
Arm/Group Description	LAI 590 mg QD Liposomal amikacin for inhalation (LAI): - Liposomal amikacin for inhalation is provided as a sterile aqueous liposomal dispersion for inhalation via nebulization. 590 mg of liposomal amikacin for inhalation is administered once daily using the PARI Investigational eFlow® Nebulizer. Administration time is approximately 13 minutes. Liposomal amikacin for inhalation will be administered for 84 days in the double-blind, randomized portion of the study. Subjects can continue with 84 additional days of dosing in the open label extension.	placebo QD placebo: - Placebo is provided as a sterile aqueous lipid dispersion for inhalation via nebulization. Administration procedures, volume and administration time are similar to LAI. Placebo will be administered for 84 days only during the double-blind, randomized portion of the study.	Total of all reporting groups
Overall Participants	44	45	89
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	58.0 (16.61)	59.1 (15.20)	58.5 (15.83)
Sex: Female, Male (Count of Participants)
Female	38 86.4%	40 88.9%	78 87.6%
Male	6 13.6%	5 11.1%	11 12.4%
Race/Ethnicity, Customized (Count of Participants)
White (not of Hispanic origin)	42 95.5%	40 88.9%	82 92.1%
Hispanic	0 0%	2 4.4%	2 2.2%
African	0 0%	1 2.2%	1 1.1%
Asian	2 4.5%	2 4.4%	4 4.5%

Outcome Measures

1. Primary Outcome

Title	Change in Semi-Quantitative Mycobacterial Culture Results From Baseline to Day 84.
Description	The endpoint used the 7-step semi-quantitative scale (SQS) for mycobacterial culture reporting in both solid and liquid growth media, with step 1 = culture negative in both solid and liquid media, step 2 = growth in liquid medium only, 3 = solid medium positive, 4 = 50 to 100 colonies in solid medium & growth in liquid, 5 = >100 to 200 colonies in solid medium & growth in liquid, 6 = >200 to 500 colonies in solid medium & growth in liquid, 7 = >500 colonies in solid medium & growth in liquid. Full scale range is 1 (best score) to 7 (worst score). The change in step measures the growth at Day 84 compared to the growth at Baseline. The negative values represent reduction in colony growth.
Time Frame	Baseline and end of double-blind phase of 84 days

Outcome Measure Data

Analysis Population Description

mITT

Arm/Group Title	LAI 590 mg QD	Placebo
Arm/Group Description	LAI 590 mg QD Liposomal amikacin for inhalation (LAI): - Liposomal amikacin for inhalation is provided as a sterile aqueous liposomal dispersion for inhalation via nebulization. 590 mg of liposomal amikacin for inhalation is administered once daily using the PARI Investigational eFlow® Nebulizer. Administration time is approximately 13 minutes. Liposomal amikacin for inhalation will be administered for 84 days in the double-blind, randomized portion of the study. Subjects can continue with 84 additional days of dosing in the open label extension.	placebo QD placebo: - Placebo is provided as a sterile aqueous lipid dispersion for inhalation via nebulization. Administration procedures, volume and administration time are similar to LAI. Placebo will be administered for 84 days only during the double-blind, randomized portion of the study.
Measure Participants	44	45
Baseline: Culture negative	5 11.4%	5 11.1%
Baseline: Growth in liquid medium only	1 2.3%	1 2.2%
Baseline: Agar positive	17 38.6%	10 22.2%
Baseline: 1+ (50-100 colonies)	2 4.5%	4 8.9%
Baseline: 2+ (> 100-200 colonies)	2 4.5%	2 4.4%
Baseline: 3+ (> 200-500 colonies)	3 6.8%	4 8.9%
Baseline: 4+ (> 500 colonies)	14 31.8%	19 42.2%
Day 84: -6 steps from baseline	1 2.3%	0 0%
Day 84: -5 steps from baseline	0 0%	0 0%
Day 84: -4 steps from baseline	1 2.3%	0 0%
Day 84: -3 steps from baseline	3 6.8%	0 0%
Day 84: -2 steps from baseline	6 13.6%	6 13.3%
Day 84: -1 step from baseline	5 11.4%	5 11.1%
Day 84: no change from baseline	23 52.3%	23 51.1%
Day 84: +1 step from baseline	2 4.5%	5 11.1%
Day 84: +2 steps from baseline	0 0%	3 6.7%
Day 84: +3 steps from baseline	1 2.3%	0 0%
Day 84: +4 steps from baseline	1 2.3%	2 4.4%
Day 84: +5 steps from baseline	0 0%	1 2.2%
Day 84: +6 steps from baseline	0 0%	0 0%
Day 84: +7 (Death)	1 2.3%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LAI 590 mg QD, Placebo
	Comments	The primary efficacy analysis tested the following hypotheses: H0: There is no difference at Day 84 between the LAI arm and the placebo arm Ha: There is a difference at Day 84 between the LAI arm and the placebo arm Statistical analysis applies to all day 84 rows.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.072
	Comments	Conducted in the mITT population using a stratified Wilcoxon rank sum test, to compare the treatment arms at a 2-sided significance level of 0.05, adjusting for the randomization strata (presence/absence of CF and MAC versus Mycobacterium abscessus).
	Method	Wilcoxon rank sum test
	Comments

2. Secondary Outcome

Title	Number of Subjects With Negative NTM Culture for the LAI Arm at Day 84 Compared to the Placebo Arm at Day 84
Description	Sputum specimens were cultured in liquid media in addition to solid media (agar). If results were negative on agar, the liquid media was held for 6 weeks before reporting as culture negative. Culture was negative when confirmed with no growth in liquid medium.
Time Frame	84 days double-blind phase

Outcome Measure Data

Analysis Population Description

mITT

Arm/Group Title	LAI 590 mg QD	Placebo
Arm/Group Description	LAI 590 mg QD Liposomal amikacin for inhalation (LAI): - Liposomal amikacin for inhalation is provided as a sterile aqueous liposomal dispersion for inhalation via nebulization. 590 mg of liposomal amikacin for inhalation is administered once daily using the PARI Investigational eFlow® Nebulizer. Administration time is approximately 13 minutes. Liposomal amikacin for inhalation will be administered for 84 days in the double-blind, randomized portion of the study. Subjects can continue with 84 additional days of dosing in the open label extension.	placebo QD placebo: - Placebo is provided as a sterile aqueous lipid dispersion for inhalation via nebulization. Administration procedures, volume and administration time are similar to LAI. Placebo will be administered for 84 days only during the double-blind, randomized portion of the study.
Measure Participants	44	45
Count of Participants [Participants]	14 31.8%	4 8.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LAI 590 mg QD, Placebo
	Comments	stratified Cochran-Mantel-Haenszel test
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

3. Secondary Outcome

Title	Time to Negative NTM Culture….During the 84-day Double-blind Treatment Phase
Description	Sputum specimens were cultured in liquid media in addition to solid media (agar). If results were negative on agar, the liquid media was held for 6 weeks before reporting as culture negative. Culture was negative when confirmed with no growth in liquid medium.
Time Frame	84 days double-blind phase

Outcome Measure Data

Analysis Population Description

mITT

Arm/Group Title	LAI 590 mg QD	Placebo
Arm/Group Description	LAI 590 mg QD Liposomal amikacin for inhalation (LAI): - Liposomal amikacin for inhalation is provided as a sterile aqueous liposomal dispersion for inhalation via nebulization. 590 mg of liposomal amikacin for inhalation is administered once daily using the PARI Investigational eFlow® Nebulizer. Administration time is approximately 13 minutes. Liposomal amikacin for inhalation will be administered for 84 days in the double-blind, randomized portion of the study. Subjects can continue with 84 additional days of dosing in the open label extension.	placebo QD placebo: - Placebo is provided as a sterile aqueous lipid dispersion for inhalation via nebulization. Administration procedures, volume and administration time are similar to LAI. Placebo will be administered for 84 days only during the double-blind, randomized portion of the study.
Measure Participants	44	45
Median (Inter-Quartile Range) [days]	NA	NA

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LAI 590 mg QD, Placebo
	Comments	Cox proportional hazard model
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0129
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	5.68
	Confidence Interval	(2-Sided) 95%; 1.25 to 25.79
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Ordinal, 3-level Response From Baseline on the SQS for Mycobacterial Culture for the LAI Arm at Day 84 Compared to the Placebo Arm at Day 84
Description	The ordinal, 3-level response are (1) improvement (2) no change (3) worsening or death
Time Frame	Baseline and end of double-blind phase of 84 days

Outcome Measure Data

Analysis Population Description

mITT

Arm/Group Title	LAI 590 mg QD	Placebo
Arm/Group Description	LAI 590 mg QD Liposomal amikacin for inhalation (LAI): - Liposomal amikacin for inhalation is provided as a sterile aqueous liposomal dispersion for inhalation via nebulization. 590 mg of liposomal amikacin for inhalation is administered once daily using the PARI Investigational eFlow® Nebulizer. Administration time is approximately 13 minutes. Liposomal amikacin for inhalation will be administered for 84 days in the double-blind, randomized portion of the study. Subjects can continue with 84 additional days of dosing in the open label extension.	placebo QD placebo: - Placebo is provided as a sterile aqueous lipid dispersion for inhalation via nebulization. Administration procedures, volume and administration time are similar to LAI. Placebo will be administered for 84 days only during the double-blind, randomized portion of the study.
Measure Participants	44	45
Improvement (a decrease of 1 step or more)	16 36.4%	11 24.4%
No change	20 45.5%	23 51.1%
Worsening (an increase of 1 step or more) or death	5 11.4%	11 24.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LAI 590 mg QD, Placebo
	Comments	Ordinal Logistic Regressions Model
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.077
	Comments
	Method	Regression, Logistic
	Comments

5. Secondary Outcome

Title	Change From Baseline in Respiratory and Systemic Symptoms Questionnaire (RSSQ) Score at Day 84 for the LAI Arm Compared to the Placebo Arm
Description	The RSSQ was administered to gather information from the subject about the types of symptoms that the subject has experienced since the last contact. A reduction in score indicates improvement. The range of values for the scores are -2 (best) to +2 (worst) in whole numbers. The composite score was calculated by averaging the scores of the subscales.
Time Frame	Baseline to day 84.

Outcome Measure Data

Analysis Population Description

mITT

Arm/Group Title	LAI 590 mg QD	Placebo
Arm/Group Description	LAI 590 mg QD Liposomal amikacin for inhalation (LAI): - Liposomal amikacin for inhalation is provided as a sterile aqueous liposomal dispersion for inhalation via nebulization. 590 mg of liposomal amikacin for inhalation is administered once daily using the PARI Investigational eFlow® Nebulizer. Administration time is approximately 13 minutes. Liposomal amikacin for inhalation will be administered for 84 days in the double-blind, randomized portion of the study. Subjects can continue with 84 additional days of dosing in the open label extension.	placebo QD placebo: - Placebo is provided as a sterile aqueous lipid dispersion for inhalation via nebulization. Administration procedures, volume and administration time are similar to LAI. Placebo will be administered for 84 days only during the double-blind, randomized portion of the study.
Measure Participants	44	45
Mean (Standard Deviation) [units on a score]	-0.80 (0.992)	-0.60 (0.736)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LAI 590 mg QD, Placebo
	Comments	Stratified Wilcoxon-rank sum
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4545
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

6. Secondary Outcome

Title	Change From Baseline in Global Rating of Health (GRH) at Day 84 for the LAI Arm Compared to the Placebo Arm
Description	The assessing physician asked the subject to rate his/her assessment of health according to the GRH. Subject responses to, "How would you rate your health at the present time?" included: Excellent, Good, Fair, or Poor.
Time Frame	Baseline and end of double-blind phase of 84 days

Outcome Measure Data

Analysis Population Description

mITT Subjects with missing data were excluded

Arm/Group Title	LAI 590 mg QD	Placebo
Arm/Group Description	LAI 590 mg QD Liposomal amikacin for inhalation (LAI): - Liposomal amikacin for inhalation is provided as a sterile aqueous liposomal dispersion for inhalation via nebulization. 590 mg of liposomal amikacin for inhalation is administered once daily using the PARI Investigational eFlow® Nebulizer. Administration time is approximately 13 minutes. Liposomal amikacin for inhalation will be administered for 84 days in the double-blind, randomized portion of the study. Subjects can continue with 84 additional days of dosing in the open label extension.	placebo QD placebo: - Placebo is provided as a sterile aqueous lipid dispersion for inhalation via nebulization. Administration procedures, volume and administration time are similar to LAI. Placebo will be administered for 84 days only during the double-blind, randomized portion of the study.
Measure Participants	44	45
No change: Excellent -> Excellent	2 4.5%	2 4.4%
No change: Good -> Good	15 34.1%	21 46.7%
No change: Fair -> Fair	8 18.2%	5 11.1%
No change: Poor -> Poor	1 2.3%	1 2.2%
Increase	4 9.1%	6 13.3%
Increase: By 3 Categories (Poor -> Excellent)	0 0%	0 0%
Increase by 2 Categories	0 0%	1 2.2%
Increase: By 2 Categories (Poor -> Good)	0 0%	0 0%
Increase: By 2 Categories (Fair -> Excellent)	0 0%	1 2.2%
Increase by 1 Category	4 9.1%	5 11.1%
Increase: By 1 Category (Poor -> Fair)	2 4.5%	0 0%
Increase: By 1 Category (Fair -> Good)	2 4.5%	5 11.1%
Increase: By 1 Category (Good -> Excellent)	0 0%	0 0%
Decrease	9 20.5%	10 22.2%
Decrease: By 3 Categories (Excellent --> Poor)	0 0%	0 0%
Decrease: By 2 Categories	0 0%	0 0%
Decrease: By 2 Categories (Excellent -> Fair)	0 0%	0 0%
Decrease: By 2 Categories (Good -> Poor)	0 0%	0 0%
Decrease: By 1 Category	9 20.5%	10 22.2%
Decrease: By 1 Category (Excellent -> Good)	2 4.5%	0 0%
Decrease: By 1 Category (Good -> Fair)	5 11.4%	7 15.6%
Decrease: By 1 Category (Fair -> Poor)	2 4.5%	3 6.7%

7. Secondary Outcome

Title	Number of Participants Requiring "Rescue" Anti-mycobacterial or Other "Rescue" Drugs During the 84-day Double-blind Phase
Description	Per the study protocol, study subjects were on a stable, multi-drug, anti-mycobacterial regimen based on the 2007 ATS/IDSA Guidelines; the regimen should not have changed during the study period except for safety concerns. The need for changes to the concurrent anti-mycobacterial regimen or "rescue" therapy was at the discretion of the Investigator and was tracked as a study outcome.
Time Frame	84 days double-blind phase

Outcome Measure Data

Analysis Population Description

mITT

Arm/Group Title	LAI 590 mg QD	Placebo
Arm/Group Description	LAI 590 mg QD Liposomal amikacin for inhalation (LAI): - Liposomal amikacin for inhalation is provided as a sterile aqueous liposomal dispersion for inhalation via nebulization. 590 mg of liposomal amikacin for inhalation is administered once daily using the PARI Investigational eFlow® Nebulizer. Administration time is approximately 13 minutes. Liposomal amikacin for inhalation will be administered for 84 days in the double-blind, randomized portion of the study. Subjects can continue with 84 additional days of dosing in the open label extension.	placebo QD placebo: - Placebo is provided as a sterile aqueous lipid dispersion for inhalation via nebulization. Administration procedures, volume and administration time are similar to LAI. Placebo will be administered for 84 days only during the double-blind, randomized portion of the study.
Measure Participants	44	45
Number [participants]	21 47.7%	11 24.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LAI 590 mg QD, Placebo
	Comments	Cox Proportional Hazard Model
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0076
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	2.69
	Confidence Interval	(2-Sided) 95%; 1.28 to 5.64
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Number of Subject for "Rescue" Anti-mycobacterial or Other "Rescue" Drugs During the 84-day Double-blind Phase
Description	Per the study protocol, study subjects were on a stable, multi-drug, anti-mycobacterial regimen based on the 2007 ATS/IDSA Guidelines; the regimen should not have changed during the study period except for safety concerns. The need for changes to the concurrent anti-mycobacterial regimen or "rescue" therapy was at the discretion of the Investigator and was tracked as a study outcome.
Time Frame	84 days double-blind phase

Outcome Measure Data

Analysis Population Description

mITT

Arm/Group Title	LAI 590 mg QD	Placebo
Arm/Group Description	LAI 590 mg QD Liposomal amikacin for inhalation (LAI): - Liposomal amikacin for inhalation is provided as a sterile aqueous liposomal dispersion for inhalation via nebulization. 590 mg of liposomal amikacin for inhalation is administered once daily using the PARI Investigational eFlow® Nebulizer. Administration time is approximately 13 minutes. Liposomal amikacin for inhalation will be administered for 84 days in the double-blind, randomized portion of the study. Subjects can continue with 84 additional days of dosing in the open label extension.	placebo QD placebo: - Placebo is provided as a sterile aqueous lipid dispersion for inhalation via nebulization. Administration procedures, volume and administration time are similar to LAI. Placebo will be administered for 84 days only during the double-blind, randomized portion of the study.
Measure Participants	44	45
Number of subjects with the event	21 47.7%	11 24.4%
Number censored	23 52.3%	34 75.6%

Adverse Events

Time Frame	Up to Day 196 (84 days double-blind phase + 84 days open label phase + 28 days post discontinuation of study drug). Adverse events (AEs) were not collected during the 12-month follow-up period..
Arm/Group Title	LAI 590 mg QD - Double Blind		Placebo - Double Blind		LAI 590 mg QD - Open Label		Placebo - Open Label
Arm/Group Description	LAI 590 mg QD Liposomal amikacin for inhalation (LAI): - Liposomal amikacin for inhalation is provided as a sterile aqueous liposomal dispersion for inhalation via nebulization. 590 mg of liposomal amikacin for inhalation is administered once daily using the PARI Investigational eFlow® Nebulizer. Administration time is approximately 13 minutes. Liposomal amikacin for inhalation will be administered for 84 days in the double-blind, randomized portion of the study. Subjects can continue with 84 additional days of dosing in the open label extension.		placebo QD placebo: - Placebo is provided as a sterile aqueous lipid dispersion for inhalation via nebulization. Administration procedures, volume and administration time are similar to LAI. Placebo will be administered for 84 days only during the double-blind, randomized portion of the study.		LAI 590 mg QD Liposomal amikacin for inhalation (LAI): - Liposomal amikacin for inhalation is provided as a sterile aqueous liposomal dispersion for inhalation via nebulization. - 590 mg of liposomal amikacin for inhalation is administered once daily using the PARI Investigational eFlow® Nebulizer. Subjects can continue with 84 additional days of dosing in the open label extension.		placebo QD placebo: - Placebo is provided as a sterile aqueous lipid dispersion for inhalation via nebulization. Subjects can continue with 84 additional days of dosing in the open label extension.
All Cause Mortality
	LAI 590 mg QD - Double Blind		Placebo - Double Blind		LAI 590 mg QD - Open Label		Placebo - Open Label
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/44 (2.3%)		0/45 (0%)		1/35 (2.9%)		0/43 (0%)
Serious Adverse Events
	LAI 590 mg QD - Double Blind		Placebo - Double Blind		LAI 590 mg QD - Open Label		Placebo - Open Label
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/44 (18.2%)		4/45 (8.9%)		5/35 (14.3%)		5/43 (11.6%)
Cardiac disorders
Supraventricular tachycardia	1/44 (2.3%)	1	0/45 (0%)	0	0/35 (0%)	0	1/43 (2.3%)	1
Acute coronary syndrome	0/44 (0%)	0	0/45 (0%)	0	1/35 (2.9%)	1	0/43 (0%)	0
Ear and labyrinth disorders
Vertigo	0/44 (0%)	0	0/45 (0%)	0	1/35 (2.9%)	1	0/43 (0%)	0
Gastrointestinal disorders
Small intestinal obstruction	0/44 (0%)	0	1/45 (2.2%)	1	0/35 (0%)	0	0/43 (0%)	0
Intestinal ischaemia	0/44 (0%)	0	0/45 (0%)	0	1/35 (2.9%)	1	0/43 (0%)	0
General disorders
Multi-organ failure	0/44 (0%)	0	0/45 (0%)	0	1/35 (2.9%)	1	0/43 (0%)	0
Infections and infestations
Infective exacerbation of bronchiectasis	2/44 (4.5%)	2	1/45 (2.2%)	1	0/35 (0%)	0	0/43 (0%)	0
Pneumonia	1/44 (2.3%)	1	2/45 (4.4%)	2	0/35 (0%)	0	0/43 (0%)	0
Gastroenteritis viral	1/44 (2.3%)	1	0/45 (0%)	0	0/35 (0%)	0	0/43 (0%)	0
Infective pulmonary exacerbation of cystic fibrosis	1/44 (2.3%)	1	0/45 (0%)	0	2/35 (5.7%)	2	3/43 (7%)	3
Urinary Tract Infection	0/44 (0%)	0	0/45 (0%)	0	1/35 (2.9%)	1	0/43 (0%)	0
Urosepsis	0/44 (0%)	0	0/45 (0%)	0	1/35 (2.9%)	1	0/43 (0%)	0
Injury, poisoning and procedural complications
Femur fracture	1/44 (2.3%)	1	0/45 (0%)	0	0/35 (0%)	0	0/43 (0%)	0
Humerus fracture	1/44 (2.3%)	1	0/45 (0%)	0	0/35 (0%)	0	0/43 (0%)	0
Metabolism and nutrition disorders
Dehydration	1/44 (2.3%)	1	0/45 (0%)	0	0/35 (0%)	0	0/43 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory distress syndrome	1/44 (2.3%)	1	0/45 (0%)	0	0/35 (0%)	0	0/43 (0%)	0
Eosinophilic pneumonia	0/44 (0%)	0	1/45 (2.2%)	1	0/35 (0%)	0	0/43 (0%)	0
Haemoptysis	1/44 (2.3%)	1	0/45 (0%)	0	0/35 (0%)	0	0/43 (0%)	0
Respiratory disorder	1/44 (2.3%)	1	0/45 (0%)	0	0/35 (0%)	0	0/43 (0%)	0
Pneumonitis	0/44 (0%)	0	0/45 (0%)	0	1/35 (2.9%)	1	1/43 (2.3%)	1
Vascular disorders
Deep Vein Thrombosis	0/44 (0%)	0	0/45 (0%)	0	1/35 (2.9%)	1	0/43 (0%)	0
Other (Not Including Serious) Adverse Events
	LAI 590 mg QD - Double Blind		Placebo - Double Blind		LAI 590 mg QD - Open Label		Placebo - Open Label
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	41/44 (93.2%)		39/45 (86.7%)		31/35 (88.6%)		42/43 (97.7%)
Ear and labyrinth disorders
Ear pain	3/44 (6.8%)	3	0/45 (0%)	0	3/35 (8.6%)	4	0/43 (0%)	0
Gastrointestinal disorders
Nausea	5/44 (11.4%)	5	4/45 (8.9%)	4	3/35 (8.6%)	3	5/43 (11.6%)	6
Abdominal discomfort	3/44 (6.8%)	3	0/45 (0%)	0	2/35 (5.7%)	2	0/43 (0%)	0
Diarrhoea	0/44 (0%)	0	3/45 (6.7%)	3	1/35 (2.9%)	1	4/43 (9.3%)	5
General disorders
Fatigue	7/44 (15.9%)	8	4/45 (8.9%)	4	0/35 (0%)	0	0/43 (0%)	0
Pyrexia	4/44 (9.1%)	5	3/45 (6.7%)	6	3/35 (8.6%)	4	1/43 (2.3%)	1
Chest discomfort	5/44 (11.4%)	5	0/45 (0%)	0	0/35 (0%)	0	0/43 (0%)	0
Infections and infestations
Infective exacerbation of bronchiectasis	17/44 (38.6%)	21	9/45 (20%)	9	9/35 (25.7%)	9	15/43 (34.9%)	16
Pneumonia	2/44 (4.5%)	2	3/45 (6.7%)	3	0/35 (0%)	0	0/43 (0%)	0
Infective pulmonary exacerbation of cystic fibrosis	3/44 (6.8%)	3	1/45 (2.2%)	1	4/35 (11.4%)	5	6/43 (14%)	8
Laryngitis	3/44 (6.8%)	3	1/45 (2.2%)	1	1/35 (2.9%)	1	4/43 (9.3%)	4
Nasopharyngitis	3/44 (6.8%)	3	0/45 (0%)	0	0/35 (0%)	0	0/43 (0%)	0
Upper Respiratory Tract Infection	0/44 (0%)	0	0/45 (0%)	0	1/35 (2.9%)	1	3/43 (7%)	3
Oral Candidiasis	0/44 (0%)	0	0/45 (0%)	0	0/35 (0%)	0	3/43 (7%)	3
Urinary Tract Infection	0/44 (0%)	0	0/45 (0%)	0	3/35 (8.6%)	3	0/43 (0%)	0
Nervous system disorders
Headache	3/44 (6.8%)	4	3/45 (6.7%)	7	2/35 (5.7%)	2	5/43 (11.6%)	5
Aphonia	0/44 (0%)	0	0/45 (0%)	0	2/35 (5.7%)	3	2/43 (4.7%)	2
Psychiatric disorders
Insomnia	3/44 (6.8%)	3	0/45 (0%)	0	0/35 (0%)	0	0/43 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dysphonia	19/44 (43.2%)	25	4/45 (8.9%)	4	3/35 (8.6%)	3	12/43 (27.9%)	12
Cough	14/44 (31.8%)	17	6/45 (13.3%)	6	3/35 (8.6%)	3	8/43 (18.6%)	10
Oropharyngeal pain	9/44 (20.5%)	9	1/45 (2.2%)	1	3/35 (8.6%)	6	3/43 (7%)	3
Haemoptysis	4/44 (9.1%)	4	5/45 (11.1%)	6	5/35 (14.3%)	5	5/43 (11.6%)	5
Wheezing	4/44 (9.1%)	4	1/45 (2.2%)	1	0/35 (0%)	0	0/43 (0%)	0
Dyspnoea	3/44 (6.8%)	4	1/45 (2.2%)	2	0/35 (0%)	0	4/43 (9.3%)	4
Nasal congestion	3/44 (6.8%)	3	0/45 (0%)	0	0/35 (0%)	0	0/43 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Per the signed Investigator Agreement in the protocol and protocol amendments, the PI agreed that the information presented in the study protocol is confidential, and assured that no information based on the conduct of the study was released without prior Insmed Incorporated Consent, unless the requirement is superseded by the Food and Drug Administration or other regulatory authority.