Liposomal Amikacin for Inhalation (LAI) for Nontuberculou... | NCT01315236

Name	Class
National Institute of Allergy and Infectious Diseases (NIAID)	NIH

Description Module

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.

Label	Type	Description	Intervention Names
LAI 590 mg QD	Experimental	LAI 590 mg QD	Drug: Liposomal amikacin for inhalation (LAI)
Placebo	Placebo Comparator	placebo QD	Drug: placebo

Name	Type	Description	Arm Group Labels	Other Names
Liposomal amikacin for inhalation (LAI)	Drug	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.

Measure	Description	Time Frame
Change in Semi-Quantitative Mycobacterial Culture Results From Baseline to Day 84.	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.	Baseline and end of double-blind phase of 84 days

Measure	Description	Time Frame
Number of Subjects With Negative NTM Culture for the LAI Arm at Day 84 Compared to the Placebo Arm at Day 84	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.	84 days double-blind phase

Eligibility Module

Eligibility Criteria

Key Inclusion Criteria:

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

Forced Expiratory Volume in 1 second (FEV1) <30% of predicted at Screening.
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.
Subjects with hemoptysis of ≥60 mL in a 24 hour period within 4 weeks prior to screening.
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.
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.
Pulmonary tuberculosis requiring treatment or treated within 2 years prior to screening.
History of lung transplantation.
Hypersensitivity to aminoglycosides.
Any change in chronic NTM multi-drug regimen within 28 days prior to Study Day 1.
Evidence of biliary cirrhosis with portal hypertension.
History of daily, continuous oxygen supplementation.
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.

Name	Affiliation	Role
Gina Eagle	Insmed Incorporated	Study Director

PubMed Identifier	Type	Citation	Retractions
33595792	Derived	Rubino CM, Onufrak NJ, van Ingen J, Griffith DE, Bhavnani SM, Yuen DW, Mange KC, Winthrop KL. Population Pharmacokinetic Evaluation of Amikacin Liposome Inhalation Suspension in Patients with Treatment-Refractory Nontuberculous Mycobacterial Lung Disease. Eur J Drug Metab Pharmacokinet. 2021 Mar;46(2):277-287. doi: 10.1007/s13318-020-00669-7. Epub 2021 Feb 17.
27748623

ID	Title	Description
FG000	LAI 590 mg QD	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.

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Change in Semi-Quantitative Mycobacterial Culture Results From Baseline to Day 84.

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.

mITT

Posted

Count of Participants

Participants

Baseline and end of double-blind phase of 84 days

ID	Title	Description
OG000	LAI 590 mg QD	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.
OG001	Placebo	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.

Units	Counts
Participants	OG00044 OG00145

Title

Denominators

Categories

Baseline: Culture negative

Title	Measurements
	OG0005 OG0015

Baseline: Growth in liquid medium only

Title	Measurements
	OG000

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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.	Wilcoxon rank sum test		0.072	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).													Superiority

Secondary

Number of Subjects With Negative NTM Culture for the LAI Arm at Day 84 Compared to the Placebo Arm at Day 84

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.

mITT

Posted

Count of Participants

Participants

84 days double-blind phase

ID	Title	Description
OG000	LAI 590 mg QD	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.
OG001	Placebo	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.

Secondary

Time to Negative NTM Culture….During the 84-day Double-blind Treatment Phase

mITT

Posted

Median

Inter-Quartile Range

days

84 days double-blind phase

ID	Title	Description
OG000	LAI 590 mg QD	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.
OG001	Placebo	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.

Secondary

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

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

mITT

Posted

Count of Participants

Participants

Baseline and end of double-blind phase of 84 days

ID	Title	Description
OG000	LAI 590 mg QD	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.
OG001	Placebo	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.

Secondary

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

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.

mITT

Posted

Mean

Standard Deviation

units on a score

Baseline to day 84.

ID	Title	Description
OG000	LAI 590 mg QD	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.
OG001	Placebo	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.

Secondary

Change From Baseline in Global Rating of Health (GRH) at Day 84 for the LAI Arm Compared to the Placebo Arm

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.

mITT

Subjects with missing data were excluded

Posted

Count of Participants

Participants

Baseline and end of double-blind phase of 84 days

ID	Title	Description
OG000	LAI 590 mg QD	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.
OG001	Placebo	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.

Secondary

Number of Participants Requiring "Rescue" Anti-mycobacterial or Other "Rescue" Drugs During the 84-day 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.

mITT

Posted

Number

participants

84 days double-blind phase

ID	Title	Description
OG000	LAI 590 mg QD	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.
OG001	Placebo	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.

Secondary

Number of Subject for "Rescue" Anti-mycobacterial or Other "Rescue" Drugs During the 84-day Double-blind Phase

mITT

Posted

Number

participants

84 days double-blind phase

ID	Title	Description
OG000	LAI 590 mg QD	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.
OG001	Placebo	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.

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Infective exacerbation of bronchiectasis	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0002 events2 affected44 at risk EG0011 events1 affected45 at risk EG0020 events0 affected35 at risk EG0030 events0 affected43 at risk
Pneumonia	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected44 at risk EG0012 events2 affected45 at risk EG0020 events0 affected35 at risk EG003
Gastroenteritis viral	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected45 at risk EG0020 events0 affected35 at risk EG003
Acute respiratory distress syndrome	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected45 at risk EG0020 events0 affected35 at risk EG003
Eosinophilic pneumonia	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected44 at risk EG0011 events1 affected45 at risk EG0020 events0 affected35 at risk EG003
Haemoptysis	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected45 at risk EG0020 events0 affected35 at risk EG003
Respiratory disorder	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected45 at risk EG0020 events0 affected35 at risk EG003
Femur fracture	Injury, poisoning and procedural complications	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected45 at risk EG0020 events0 affected35 at risk EG003
Humerus fracture	Injury, poisoning and procedural complications	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected45 at risk EG0020 events0 affected35 at risk EG003
Supraventricular tachycardia	Cardiac disorders	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected45 at risk EG0020 events0 affected35 at risk EG003
Small intestinal obstruction	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected44 at risk EG0011 events1 affected45 at risk EG0020 events0 affected35 at risk EG003
Dehydration	Metabolism and nutrition disorders	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected45 at risk EG0020 events0 affected35 at risk EG003
Infective pulmonary exacerbation of cystic fibrosis	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0001 events1 affected44 at risk EG0010 events0 affected45 at risk EG0022 events2 affected35 at risk EG003
Urinary Tract Infection	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected44 at risk EG0010 events0 affected45 at risk EG0021 events1 affected35 at risk EG003
Urosepsis	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected44 at risk EG0010 events0 affected45 at risk EG0021 events1 affected35 at risk EG003
Acute coronary syndrome	Cardiac disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected44 at risk EG0010 events0 affected45 at risk EG0021 events1 affected35 at risk EG003
Pneumonitis	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected44 at risk EG0010 events0 affected45 at risk EG0021 events1 affected35 at risk EG003
Vertigo	Ear and labyrinth disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected44 at risk EG0010 events0 affected45 at risk EG0021 events1 affected35 at risk EG003
Intestinal ischaemia	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected44 at risk EG0010 events0 affected45 at risk EG0021 events1 affected35 at risk EG003
Multi-organ failure	General disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected44 at risk EG0010 events0 affected45 at risk EG0021 events1 affected35 at risk EG003
Deep Vein Thrombosis	Vascular disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected44 at risk EG0010 events0 affected45 at risk EG0021 events1 affected35 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Ear pain	Ear and labyrinth disorders	MedDRA 15.0	Systematic Assessment	EG0003 events3 affected44 at risk EG0010 events0 affected45 at risk EG0024 events3 affected35 at risk EG0030 events0 affected43 at risk
Nausea	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0005 events5 affected44 at risk EG0014 events4 affected45 at risk EG0023 events3 affected35 at risk EG003
Abdominal discomfort	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0003 events3 affected44 at risk EG0010 events0 affected45 at risk EG0022 events2 affected35 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected44 at risk EG0013 events3 affected45 at risk EG0021 events1 affected35 at risk EG003
Fatigue	General disorders	MedDRA 15.0	Systematic Assessment	EG0008 events7 affected44 at risk EG0014 events4 affected45 at risk EG0020 events0 affected35 at risk EG003
Pyrexia	General disorders	MedDRA 15.0	Systematic Assessment	EG0005 events4 affected44 at risk EG0016 events3 affected45 at risk EG0024 events3 affected35 at risk EG003
Chest discomfort	General disorders	MedDRA 15.0	Systematic Assessment	EG0005 events5 affected44 at risk EG0010 events0 affected45 at risk EG0020 events0 affected35 at risk EG003
Infective exacerbation of bronchiectasis	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG00021 events17 affected44 at risk EG0019 events9 affected45 at risk EG0029 events9 affected35 at risk EG003
Pneumonia	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0002 events2 affected44 at risk EG0013 events3 affected45 at risk EG0020 events0 affected35 at risk EG003
Infective pulmonary exacerbation of cystic fibrosis	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0003 events3 affected44 at risk EG0011 events1 affected45 at risk EG0025 events4 affected35 at risk EG003
Laryngitis	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0003 events3 affected44 at risk EG0011 events1 affected45 at risk EG0021 events1 affected35 at risk EG003
Nasopharyngitis	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0003 events3 affected44 at risk EG0010 events0 affected45 at risk EG0020 events0 affected35 at risk EG003
Headache	Nervous system disorders	MedDRA 15.0	Systematic Assessment	EG0004 events3 affected44 at risk EG0017 events3 affected45 at risk EG0022 events2 affected35 at risk EG003
Insomnia	Psychiatric disorders	MedDRA 15.0	Systematic Assessment	EG0003 events3 affected44 at risk EG0010 events0 affected45 at risk EG0020 events0 affected35 at risk EG003
Dysphonia	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG00025 events19 affected44 at risk EG0014 events4 affected45 at risk EG0023 events3 affected35 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG00017 events14 affected44 at risk EG0016 events6 affected45 at risk EG0023 events3 affected35 at risk EG003
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG0009 events9 affected44 at risk EG0011 events1 affected45 at risk EG0026 events3 affected35 at risk EG003
Haemoptysis	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG0004 events4 affected44 at risk EG0016 events5 affected45 at risk EG0025 events5 affected35 at risk EG003
Wheezing	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG0004 events4 affected44 at risk EG0011 events1 affected45 at risk EG0020 events0 affected35 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG0004 events3 affected44 at risk EG0012 events1 affected45 at risk EG0020 events0 affected35 at risk EG003
Nasal congestion	Respiratory, thoracic and mediastinal disorders	MedDRA 15.0	Systematic Assessment	EG0003 events3 affected44 at risk EG0010 events0 affected45 at risk EG0020 events0 affected35 at risk EG003
Upper Respiratory Tract Infection	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected44 at risk EG0010 events0 affected45 at risk EG0021 events1 affected35 at risk EG003
Oral Candidiasis	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected44 at risk EG0010 events0 affected45 at risk EG0020 events0 affected35 at risk EG003
Urinary Tract Infection	Infections and infestations	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected44 at risk EG0010 events0 affected45 at risk EG0023 events3 affected35 at risk EG003
Aphonia	Nervous system disorders	MedDRA 15.0	Systematic Assessment	EG0000 events0 affected44 at risk EG0010 events0 affected45 at risk EG0023 events2 affected35 at risk EG003

Facility	Status	City	State	ZIP	Country	Contacts
		Birmingham	Alabama		United States

ID	Term
D009164	Mycobacterium Infections
D000193	Actinomycetales Infections
D016908	Gram-Positive Bacterial Infections
D001424	Bacterial Infections
D001423	Bacterial Infections and Mycoses
D007239	Infections

ID	Term
D015656	Respiratory Mechanics
D012119	Respiration
D012143	Respiratory Physiological Phenomena
D002943	Circulatory and Respiratory Physiological Phenomena

ID	Title	Description
BG000	LAI 590 mg QD	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.
BG001	Placebo	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.
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	LAI 590 mg QD - Double Blind	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.	1	44	8	44	41	44
EG001	Placebo - Double Blind	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.	0	45	4	45	39	45
EG002	LAI 590 mg QD - Open Label	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.	1	35	5	35	31	35
EG003	Placebo - Open Label	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.	0	43	5	43	42	43