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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Active Comparator, Multicenter Study to Validate Patient-Reported Outcome Instruments in Adult Subjects with Newly Diagnosed Nontuberculous Mycobacterial (NTM) Lung Infection Caused by Mycobacterium avium Complex (MAC)

    Summary
    EudraCT number
    		 2020-002545-42
    Trial protocol
    		 DK   DE   HU   AT   NL   GR   IT  
    Global end of trial date
    09 May 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 May 2024
    First version publication date
    24 May 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    INS-415
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04677543
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Insmed Incorporated
    Sponsor organisation address
    700 US Highway 202/206, Bridgewater, NJ, United States, 08807-1704
    Public contact
    Insmed Medical Information, Insmed Incorporated, medicalinformation@Insmed.com
    Scientific contact
    Insmed Medical Information, Insmed Incorporated, medicalinformation@insmed.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 May 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 May 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study was to generate evidence demonstrating the domain specification (via modern psychometric methods), reliability, validity, and responsiveness (within-subject meaningful change) of the Patient-Reported Outcome (PRO) endpoints.
    Protection of trial subjects
    This study was conducted in compliance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP), including the archiving of essential documents.
    Background therapy
    		 Background Regimen (Azithromycin + Ethambutol)
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Dec 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Korea, Republic of: 7
    Country: Number of subjects enrolled
    New Zealand: 3
    Country: Number of subjects enrolled
    Taiwan: 8
    Country: Number of subjects enrolled
    United States: 39
    Worldwide total number of subjects
    99
    EEA total number of subjects
    32
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    32
    From 65 to 84 years
    65
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in this multi-centre study at different investigative sites from 22 December 2020 to 09 May 2023.

    Pre-assignment
    Screening details
    		 A total of 99 participants with mycobacterium avium complex (MAC) lung infection were enrolled in the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Carer, Data analyst, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ALIS + Background Regimen (Azithromycin + Ethambutol)
    Arm description
    		 Participants received 590 mg of amikacin liposome inhalation suspension (ALIS) once daily. Participants also received the background regimen of azithromycin 250 mg and ethambutol 15 milligrams per kilogram (mg/kg) tablets orally, once daily.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Amikacin Liposome Inhalation Suspension
    Investigational medicinal product code
    Other name
    ALIS, ARIKAYCE®
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    ALIS 590 mg once daily

    Arm title
    		 ELC + Background Regimen (Azithromycin + Ethambutol)
    Arm description
    		 Participants received empty liposome control (ELC), a matching placebo to ALIS, once daily. Participants also received the background regimen of azithromycin 250 mg and ethambutol 15 mg/kg tablets orally, once daily.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Empty Liposome Control
    Investigational medicinal product code
    Other name
    ELC
    Pharmaceutical forms
    Inhalation solution
    Routes of administration
    Inhalation use
    Dosage and administration details
    ELC, a matching placebo to ALIS, once daily.

    Number of subjects in period 1
    		ALIS + Background Regimen (Azithromycin + Ethambutol) ELC + Background Regimen (Azithromycin + Ethambutol)
    Started
    48
    51
    Completed
    44
    48
    Not completed
    4
    3
         Consent withdrawn by subject
    4
    1
         Physician decision
    -
    1
         Adverse event, non-fatal
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ALIS + Background Regimen (Azithromycin + Ethambutol)
    Reporting group description
    		 Participants received 590 mg of amikacin liposome inhalation suspension (ALIS) once daily. Participants also received the background regimen of azithromycin 250 mg and ethambutol 15 milligrams per kilogram (mg/kg) tablets orally, once daily.

    Reporting group title
    ELC + Background Regimen (Azithromycin + Ethambutol)
    Reporting group description
    		 Participants received empty liposome control (ELC), a matching placebo to ALIS, once daily. Participants also received the background regimen of azithromycin 250 mg and ethambutol 15 mg/kg tablets orally, once daily.

    Reporting group values
    		 ALIS + Background Regimen (Azithromycin + Ethambutol) ELC + Background Regimen (Azithromycin + Ethambutol) Total
    Number of subjects
    		 48 51 99
    Age categorical
    Units: Subjects
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 69.0 ( 9.51 ) 65.9 ( 12.27 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 32 45 77
        Male
    		 16 6 22
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 6 12 18
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 1 0 1
        White
    		 41 39 80
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 3 3 6
        Not Hispanic or Latino
    		 45 48 93
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    ALIS + Background Regimen (Azithromycin + Ethambutol)
    Reporting group description
    		 Participants received 590 mg of amikacin liposome inhalation suspension (ALIS) once daily. Participants also received the background regimen of azithromycin 250 mg and ethambutol 15 milligrams per kilogram (mg/kg) tablets orally, once daily.

    Reporting group title
    ELC + Background Regimen (Azithromycin + Ethambutol)
    Reporting group description
    		 Participants received empty liposome control (ELC), a matching placebo to ALIS, once daily. Participants also received the background regimen of azithromycin 250 mg and ethambutol 15 mg/kg tablets orally, once daily.

    Primary: Psychometric Cross-Sectional Validation of Patient Reported Outcome (PRO): Patient Global Impression of Severity (PGI-S) Respiratory Scale Score at Baseline

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    End point title
    		 Psychometric Cross-Sectional Validation of Patient Reported Outcome (PRO): Patient Global Impression of Severity (PGI-S) Respiratory Scale Score at Baseline [1]
    End point description
    The PGI-S respiratory symptom is a self-reported scale to measure the severity of illness based on symptoms using a 5-point scale ranging from 1 to 5, (1=not at all, 2=mild, 3=moderate, 4=very severe, 5=extremely severe). Considering different aspects of breathing symptoms like congestion, cough, mucus, wheezing, shortness of breath, participants rated their symptom severity on the PGI-S respiratory symptom scale. Higher scores indicate greater symptom severity. ITT Analysis Set comprises all participants who were randomised.
    End point type
    Primary
    End point timeframe
    Baseline
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistical data were planned for this endpoint.
    End point values
    		 ALIS + Background Regimen (Azithromycin + Ethambutol) ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects analysed
    48
    51
    Units: score on scale
        arithmetic mean (standard deviation)
    2.5 ( 0.82 )
    2.4 ( 0.90 )
    No statistical analyses for this end point

    Primary: Psychometric Cross-Sectional Validation of PRO: PGI-S Fatigue Scale Score at Baseline

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    End point title
    		 Psychometric Cross-Sectional Validation of PRO: PGI-S Fatigue Scale Score at Baseline [2]
    End point description
    The PGI-S fatigue is a self-reported scale to measure the severity of illness based on symptoms using a 5-point scale ranging from 1 to 5, (1=not at all, 2=mild, 3=moderate, 4=very severe, 5=extremely severe). Participants rated the severity of their fatigue on the PGI-S fatigue scale. Higher scores indicate greater fatigue severity. ITT Analysis Set comprises all participants who were randomised.
    End point type
    Primary
    End point timeframe
    Baseline
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistical data were planned for this endpoint.
    End point values
    		 ALIS + Background Regimen (Azithromycin + Ethambutol) ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects analysed
    48
    51
    Units: score on scale
        arithmetic mean (standard deviation)
    2.5 ( 0.99 )
    2.5 ( 0.81 )
    No statistical analyses for this end point

    Primary: Assessment of TRTR Reported as the ICC Coefficient Estimate Among Participants Reporting no Change on Fatigue PGI-S Score Applied to PROMIS F-SF 7a Score Between Screening and Baseline

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    End point title
    		 Assessment of TRTR Reported as the ICC Coefficient Estimate Among Participants Reporting no Change on Fatigue PGI-S Score Applied to PROMIS F-SF 7a Score Between Screening and Baseline [3]
    End point description
    TRTR consists of measuring degree to which an instrument yield reproducible score at different points in time assessed across a fixed and common time interval for all subjects. TRTR co-relations were based on two-way mixed effect intraclass co-relation coefficient estimated using inter-rater reliability package, version 0.84.1. TRTR estimate of 0.7 and above indicated better retest reliability. TRTR was estimated using mean PROMIS F-SF 7a scores from participants who were stable as defined by a PGI-S-Fatigue change score of zero between screening and baseline. As pre-specified in SAP, to adequately power planned MPMs cross-sectional validation sample was composed of a total of 98 participants enrolled in INS-415 study who provided item-level PROMIS F-SF 7a data and Screening/Baseline data from first 132 participants enrolled in INS-416 study to yield a total sample of n=230. Due to EudraCT database constraints data cannot be entered here, please refer to the table attachment.
    End point type
    Primary
    End point timeframe
    From Screening to Baseline (Day -70 to Day 1)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistical data were planned for this endpoint.
    End point values
    		 ALIS + Background Regimen (Azithromycin + Ethambutol) ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: ICC estimate
        number (not applicable)
    Attachments
    		 Untitled (Filename: Assessment_of_TRTR_Reported_as_the_Intraclass_Co-relation_Coefficient_Estimate_PROMIS_F-SF_7a.pdf)
    Notes
    [4] - Data is not presented due to EudraCT database constraints.
    [5] - Data is not presented due to EudraCT database constraints.
    No statistical analyses for this end point

    Primary: Response Rate as Assessed by Within-Subject Meaningful Change (WSMC) for QOL-B Respiratory Symptoms Final Score Estimated via Anchor-Based Methods and Validated via Empirical Cumulative Distribution Functions (eCDFs)

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    End point title
    		 Response Rate as Assessed by Within-Subject Meaningful Change (WSMC) for QOL-B Respiratory Symptoms Final Score Estimated via Anchor-Based Methods and Validated via Empirical Cumulative Distribution Functions (eCDFs)
    End point description
    WSMC was estimated via change scores computed between Baseline and end of study (EOS) (Month 7). The estimated WSMC threshold of 14.81 points for the QOL-B Respiratory Symptom score (9-item scale ranging from 0 to 100, higher scores=fewer symptoms and better quality of life) as derived from anchor-based methods supplemented with eCDF curves was used for analysis. The percentage of participants and confidence intervals were estimated by standardized logistic regression with treatment group and history of mycobacterium avium complex (MAC) lung infection as factors in the model. Missing change from baseline at Month 7 was imputed by multiple imputation. The mean of all imputed values was used to derive response according to WSMC. Response rate was expressed in terms of percentage of participants and the percentages are rounded off to the nearest decimal. The ITT Analysis Set comprises all participants who were randomised.
    End point type
    Primary
    End point timeframe
    Baseline to Month 7
    End point values
    		 ALIS + Background Regimen (Azithromycin + Ethambutol) ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects analysed
    48
    51
    Units: percentage of participants
        number (confidence interval 95%)
    43.8 (29.8 to 57.8)
    33.3 (20.4 to 46.2)
    Statistical analysis title
    		 ALIS vs ELC
    Comparison groups
    ELC + Background Regimen (Azithromycin + Ethambutol) v ALIS + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2819
    Method
    		 Standardized Logistic Regression
    Parameter type
    		 Percentage Difference
    Point estimate
    10.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.6
         upper limit
    		 29.5

    Primary: Psychometric Cross-Sectional Validation of PRO: Quality of Life Questionnaire - Bronchiectasis (QoL-B) Respiratory Symptoms Scale Score at Baseline

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    End point title
    		 Psychometric Cross-Sectional Validation of PRO: Quality of Life Questionnaire - Bronchiectasis (QoL-B) Respiratory Symptoms Scale Score at Baseline [6]
    End point description
    The QOL-B is a self-administered, PRO questionnaire used to assess symptoms, functioning, and health related quality of life in adults with lung conditions. The respiratory symptom domain of the QOL-B contains 9 items describing patient's self-assessment of her/his respiratory symptoms that affect daily life. For each of the 8 items (chest congestion, coughing, cough up mucus, shortness of breath with greater activity, wheezing, chest pain, shortness of breath when talking, woken up during night due to cough), scores ranged from 1 to 4(1=lot, 2=moderate, 3=little, 4=not at all) and the sputum item based on the color ranged from 0=don't know,1=green with traces of blood/brownish dark,2=yellowish-green,3=clear to yellow,4=clear. The item scores were summed and then standardized on a 0 to 100-point scale to derive the domain score with higher scores representing fewer symptoms or better functioning and quality of life. The ITT Analysis Set comprises all participants who were randomised.
    End point type
    Primary
    End point timeframe
    Baseline
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistical data were planned for this endpoint.
    End point values
    		 ALIS + Background Regimen (Azithromycin + Ethambutol) ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects analysed
    48
    51
    Units: score on scale
        arithmetic mean (standard deviation)
    63.04 ( 14.824 )
    66.90 ( 15.673 )
    No statistical analyses for this end point

    Primary: Psychometric Cross-Sectional Validation of PRO: Patient-Reported Outcome Measurement Information System - Fatigue-Short Form 7a (PROMIS F-SF 7a) Score at Baseline

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    End point title
    		 Psychometric Cross-Sectional Validation of PRO: Patient-Reported Outcome Measurement Information System - Fatigue-Short Form 7a (PROMIS F-SF 7a) Score at Baseline [7]
    End point description
    The PROMIS F-SF 7a is a self-administered questionnaire assessing a range of self-reported symptoms over the past 7 days, from mild subjective feelings of tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that likely decreases one’s ability to execute daily activities and function normally in family or social roles. Fatigue is divided into the experience of fatigue (frequency, duration, and intensity) and the impact of fatigue on physical, mental, and social activities over 7 items. Response options are on a 5-point Likert scale, ranging from 1=never to 5=always. Total scores range from 7 to 35 and low scores represent less fatigue interference i.e., better symptoms. The ITT Analysis Set comprises all participants who were randomised.
    End point type
    Primary
    End point timeframe
    Baseline
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistical data were planned for this endpoint.
    End point values
    		 ALIS + Background Regimen (Azithromycin + Ethambutol) ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects analysed
    48
    51
    Units: score on scale
        arithmetic mean (standard deviation)
    18.3 ( 5.76 )
    18.6 ( 4.76 )
    No statistical analyses for this end point

    Primary: Assessment of Test-Retest Reliability (TRTR) Reported as the Intraclass Co-relation (ICC) Estimate Among Participants Reporting no Change on Respiratory PGI-S Score Applied to QOL-B Respiratory Domain Score Between Screening and Baseline

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    End point title
    		 Assessment of Test-Retest Reliability (TRTR) Reported as the Intraclass Co-relation (ICC) Estimate Among Participants Reporting no Change on Respiratory PGI-S Score Applied to QOL-B Respiratory Domain Score Between Screening and Baseline [8]
    End point description
    TRTR consists of measuring degree to which instrument yield reproducible score at different points in time assessed across fixed and common time interval for all subjects.TRTR was assessed among subjects reporting no change on PGI-S between screening and baseline.PGI-S anchors are PRO specific,with respiratory PGI-S(scale ranging from 1=not at all to 5=extremely severe,Higher scores=greater symptom severity) applied to QOL-B respiratory domain(9-item scale ranging from 0 to 100,higher scores=fewer symptoms and better quality of life).As pre-specified in SAP,to adequately power planned modern psychometric methods(MPMs)cross-sectional validation sample was composed of a total of 97 subjects enrolled in INS-415 study who provided item-level QOL-B Respiratory domain data and Screening/Baseline data from first 132 subjects enrolled in INS-416 study(NCT04677569) to yield a total sample of n=229.Due to EudraCT database constraints data cannot be entered here,refer to table attachment.
    End point type
    Primary
    End point timeframe
    From Screening to Baseline (Day -70 to Day 1)
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistical data were planned for this endpoint.
    End point values
    		 ALIS + Background Regimen (Azithromycin + Ethambutol) ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: ICC estimate
        number (not applicable)
    Attachments
    		 Untitled (Filename: Assessment_of_TRTR_Reported_as_the_Intraclass_Co-relation_Coefficient_Estimate_QOL-B_Respiratory.pdf)
    Notes
    [9] - Data is not presented due to EudraCT database constraints.
    [10] - Data is not presented due to EudraCT database constraints.
    No statistical analyses for this end point

    Primary: Response Rate as Assessed by WSMC for PROMIS Fatigue Final Score Estimated via Anchor-Based Methods and Validated via eCDFs

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    End point title
    		 Response Rate as Assessed by WSMC for PROMIS Fatigue Final Score Estimated via Anchor-Based Methods and Validated via eCDFs
    End point description
    WSMC was estimated via change scores computed between Baseline and EOS (Month 7). The percentage of participants and confidence intervals were estimated by standardized logistic regression with treatment group and history of MAC lung infection as factors in the model. Missing change from baseline at Month 7 was imputed by multiple imputation. The mean of all imputed values was used to derive response according to WSMC. The estimated WSMC threshold of -4.00 points for the PROMIS Fatigue score as derived from anchor-based methods supplemented with eCDF curves was used for analysis. Response rate was expressed in terms of percentage of participants and the percentages are rounded off to the nearest decimal. The ITT Analysis Set comprises all participants who were randomised.
    End point type
    Primary
    End point timeframe
    Baseline to Month 7
    End point values
    		 ALIS + Background Regimen (Azithromycin + Ethambutol) ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects analysed
    48
    51
    Units: percentage of participants
        number (confidence interval 95%)
    35.5 (22.2 to 48.7)
    29.4 (17.1 to 41.6)
    Statistical analysis title
    		 ALIS vs ELC
    Comparison groups
    ALIS + Background Regimen (Azithromycin + Ethambutol) v ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.508
    Method
    		 Standardized Logistic Regression
    Parameter type
    		 Percentage Difference
    Point estimate
    6.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.9
         upper limit
    		 24.1

    Secondary: Percentage of Participants Achieving Culture Conversion by Month 6

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    End point title
    		 Percentage of Participants Achieving Culture Conversion by Month 6
    End point description
    Culture conversion by Month 6 was defined as no MAC growth on agar media and broth media in all sputum cultures at 2 consecutive visits up to Month 6. Percentage of participants and confidence intervals were estimated by standardized logistic regression with treatment group and history of MAC lung infection as factors in the model. For the purpose of the estimation missing conversion status by Month 6 was imputed by multiple imputation. Percentages are rounded off to the nearest decimal. The ITT Analysis Set comprises all participants who were randomised.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 6
    End point values
    		 ALIS + Background Regimen (Azithromycin + Ethambutol) ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects analysed
    48
    51
    Units: percentage of participants
        number (confidence interval 95%)
    80.6 (68.7 to 92.6)
    63.9 (50.2 to 77.6)
    Statistical analysis title
    		 ALIS vs ELC
    Comparison groups
    ALIS + Background Regimen (Azithromycin + Ethambutol) v ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0712
    Method
    		 Standardized Logistic Regression
    Parameter type
    		 Percentage Difference
    Point estimate
    16.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 34.9

    Secondary: Change from Baseline in QOL-B Respiratory Symptom Score at Month 7

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    End point title
    		 Change from Baseline in QOL-B Respiratory Symptom Score at Month 7
    End point description
    QOL-B is a self-administered, PRO questionnaire used to assess symptoms, functioning, and health related quality of life in adults with lung conditions. Respiratory symptom domain of QOL-B contains 9 items describing patient's self-assessment of her/his respiratory symptoms that affect daily life. For each of the 8 items(chest congestion, coughing, cough up mucus, shortness of breath with greater activity, wheezing, chest pain, shortness of breath when talking, woken up during night due to cough), scores ranged from 1 to 4(1= lot, 2= moderate, 3= little, 4= not at all) and sputum item based on color ranged from 0=don't know,1=green with traces of blood/brownish dark,2=yellowish-green,3=clear to yellow,4=clear.Item scores were summed and then standardized on a 0 to 100-point scale to derive domain score with higher scores representing fewer symptoms or better functioning and quality of life. The ITT Analysis Set comprises all participants who were randomised.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 7
    End point values
    		 ALIS + Background Regimen (Azithromycin + Ethambutol) ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects analysed
    48
    51
    Units: score on scale
        least squares mean (confidence interval 95%)
    12.24 (7.96 to 16.53)
    7.76 (3.76 to 11.77)
    Statistical analysis title
    		 ALIS vs ELC
    Comparison groups
    ALIS + Background Regimen (Azithromycin + Ethambutol) v ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1073
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    4.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.97
         upper limit
    		 9.93

    Secondary: Time to First Negative Culture

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    End point title
    		 Time to First Negative Culture
    End point description
    Time to first negative culture was the number of months from the date of first dose of study drug(s) to the date of first MAC culture negative post-baseline. Participants without negative culture were considered censored at the last visit with available culture assessment or at Month 7 whichever occurred first. The ITT Analysis Set comprises all participants who were randomised. Number of subjects analysed is the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 7
    End point values
    		 ALIS + Background Regimen (Azithromycin + Ethambutol) ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects analysed
    45
    44
    Units: months
        median (full range (min-max))
    1.0 (1 to 3)
    1.0 (1 to 7)
    Statistical analysis title
    		 ALIS vs ELC
    Comparison groups
    ALIS + Background Regimen (Azithromycin + Ethambutol) v ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1583
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.89
         upper limit
    		 2.06

    Secondary: Change from Baseline in PROMIS F-SF 7a Score at Month 7

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    End point title
    		 Change from Baseline in PROMIS F-SF 7a Score at Month 7
    End point description
    The PROMIS F-SF 7a is a self-administered questionnaire assessing a range of self-reported symptoms over the past 7 days, from mild subjective feelings of tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that likely decreases one’s ability to execute daily activities and function normally in family or social roles. Fatigue is divided into the experience of fatigue (frequency, duration, and intensity) and the impact of fatigue on physical, mental, and social activities over 7 items. Response options are on a 5-point Likert scale, ranging from 1=never to 5=always. Total scores range from 7 to 35 and low scores represent less fatigue interference i.e., better symptoms. The ITT Analysis Set comprises all participants who were randomised.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 7
    End point values
    		 ALIS + Background Regimen (Azithromycin + Ethambutol) ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects analysed
    48
    51
    Units: score on a scale
        least squares mean (confidence interval 95%)
    -2.1 (-3.4 to -0.8)
    -1.6 (-2.9 to -0.3)
    Statistical analysis title
    		 ALIS vs ELC
    Comparison groups
    ALIS + Background Regimen (Azithromycin + Ethambutol) v ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.613
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.2
         upper limit
    		 1.3

    Secondary: Time to First Culture Conversion

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    End point title
    		 Time to First Culture Conversion
    End point description
    Time to first culture conversion was the number of months between first study drug intake and date of the first negative culture at or before Month 6 after adjustment for non-productivity. Participants without conversion at or before Month 6 are considered censored at the last visit with available culture assessment at or before Month 6. The ITT Analysis Set comprises all participants who were randomised. Number of subjects analysed is the number of participants with culture conversion who had data available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 6
    End point values
    		 ALIS + Background Regimen (Azithromycin + Ethambutol) ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects analysed
    39
    40
    Units: months
        median (full range (min-max))
    1.0 (1 to 5)
    2.0 (1 to 5)
    Statistical analysis title
    		 ALIS vs ELC
    Comparison groups
    ALIS + Background Regimen (Azithromycin + Ethambutol) v ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3542
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.79
         upper limit
    		 1.92

    Secondary: Number of Participants Who Experience any Treatment-emergent Adverse Event (TEAE)

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    End point title
    		 Number of Participants Who Experience any Treatment-emergent Adverse Event (TEAE)
    End point description
    An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. TEAEs are AEs that occurred on or after the date of first dose of study drugs and within 28 days after the end of treatment. The Safety Analysis Set comprises all participants who were randomised and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 7
    End point values
    		 ALIS + Background Regimen (Azithromycin + Ethambutol) ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects analysed
    48
    51
    Units: participants
    44
    41
    No statistical analyses for this end point

    Secondary: Recurrence of MAC (New Infection) Assessed as Percentage of Participants Who Achieved Culture Conversion With a Subsequent at Least One MAC Positive Culture in Agar Media or Broth Media in at Least 2 Consecutive Visits

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    End point title
    		 Recurrence of MAC (New Infection) Assessed as Percentage of Participants Who Achieved Culture Conversion With a Subsequent at Least One MAC Positive Culture in Agar Media or Broth Media in at Least 2 Consecutive Visits
    End point description
    Culture conversion for this outcome measure was defined as MAC culture negative at 2 consecutive visits before or at Month 5 during the treatment period. The positive culture was defined as at least 1 MAC positive culture in agar media or positive cultures in broth media in at least 2 consecutive visits. Percentages are rounded off to the nearest decimal. The ITT Analysis Set comprises all participants who were randomised. Number of subjects analysed is the number of participants who had conversion before or at Month 5 with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 7
    End point values
    		 ALIS + Background Regimen (Azithromycin + Ethambutol) ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects analysed
    39
    40
    Units: percentage of participants
        number (not applicable)
    5.1
    25.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Develop a MAC Isolate With Amikacin Minimum Inhibitory Concentration (MIC) ≥ 128 micrograms per millliliter (µg/mL) at More Than 1 Visit

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    End point title
    		 Percentage of Participants Who Develop a MAC Isolate With Amikacin Minimum Inhibitory Concentration (MIC) ≥ 128 micrograms per millliliter (µg/mL) at More Than 1 Visit
    End point description
    The ITT Analysis Set comprises all participants who were randomised.
    End point type
    Secondary
    End point timeframe
    Up to Month 7
    End point values
    		 ALIS + Background Regimen (Azithromycin + Ethambutol) ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects analysed
    48
    51
    Units: percentage of participants
    0
    0
    No statistical analyses for this end point

    Secondary: Recurrence of MAC (Relapse) Assessed as Percentage of Participants Who Achieved Culture Conversion With a Subsequent at Least One MAC Positive Culture in Agar Media or Broth Media in at Least 2 Consecutive Visits

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    End point title
    		 Recurrence of MAC (Relapse) Assessed as Percentage of Participants Who Achieved Culture Conversion With a Subsequent at Least One MAC Positive Culture in Agar Media or Broth Media in at Least 2 Consecutive Visits
    End point description
    Culture conversion for this outcome measure was defined as MAC culture negative at 2 consecutive visits before or at Month 5 during the treatment period. The positive culture was defined as at least 1 MAC positive culture in agar media or positive cultures in broth media in at least 2 consecutive visits. Percentages are rounded off to the nearest decimal. The ITT Analysis Set comprises all participants who were randomised. Number of subjects analysed is the number of participants who had conversion before or at Month 5 with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Baseline to Month 7
    End point values
    		 ALIS + Background Regimen (Azithromycin + Ethambutol) ELC + Background Regimen (Azithromycin + Ethambutol)
    Number of subjects analysed
    39
    40
    Units: percentage of participants
        number (not applicable)
    5.1
    22.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to Month 7
    Adverse event reporting additional description
    The Safety Analysis Set comprises all participants who were randomised and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    ELC + Background Regimen (Azithromycin + Ethambutol)
    Reporting group description
    		 Participants received ELC, a matching placebo to ALIS, once daily. Participants also received the background regimen of azithromycin 250 mg and ethambutol 15 mg/kg tablets orally, once daily.

    Reporting group title
    ALIS + Background Regimen (Azithromycin + Ethambutol)
    Reporting group description
    		 Participants received 590 mg of ALIS once daily. Participants also received the background regimen of azithromycin 250 mg and ethambutol 15 mg/kg tablets orally, once daily.

    Serious adverse events
    		 ELC + Background Regimen (Azithromycin + Ethambutol) ALIS + Background Regimen (Azithromycin + Ethambutol)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 51 (5.88%)
    7 / 48 (14.58%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 31
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Rhinovirus infection
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective exacerbation of bronchiectasis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 48 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 48 (2.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ELC + Background Regimen (Azithromycin + Ethambutol) ALIS + Background Regimen (Azithromycin + Ethambutol)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 51 (64.71%)
    38 / 48 (79.17%)
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 51 (0.00%)
    4 / 48 (8.33%)
         occurrences all number
    0
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 51 (9.80%)
    2 / 48 (4.17%)
         occurrences all number
    5
    3
    Headache
         subjects affected / exposed
    6 / 51 (11.76%)
    5 / 48 (10.42%)
         occurrences all number
    8
    7
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 51 (11.76%)
    5 / 48 (10.42%)
         occurrences all number
    6
    7
    Asthenia
         subjects affected / exposed
    5 / 51 (9.80%)
    2 / 48 (4.17%)
         occurrences all number
    5
    2
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    4 / 51 (7.84%)
    2 / 48 (4.17%)
         occurrences all number
    4
    2
    Eye disorders
    Vision blurred
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 48 (0.00%)
         occurrences all number
    3
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 51 (1.96%)
    4 / 48 (8.33%)
         occurrences all number
    1
    4
    Abdominal pain
         subjects affected / exposed
    4 / 51 (7.84%)
    4 / 48 (8.33%)
         occurrences all number
    4
    4
    Nausea
         subjects affected / exposed
    4 / 51 (7.84%)
    5 / 48 (10.42%)
         occurrences all number
    4
    5
    Diarrhoea
         subjects affected / exposed
    13 / 51 (25.49%)
    13 / 48 (27.08%)
         occurrences all number
    15
    22
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    2 / 51 (3.92%)
    20 / 48 (41.67%)
         occurrences all number
    2
    31
    Cough
         subjects affected / exposed
    4 / 51 (7.84%)
    13 / 48 (27.08%)
         occurrences all number
    4
    18
    Dyspnoea
         subjects affected / exposed
    4 / 51 (7.84%)
    5 / 48 (10.42%)
         occurrences all number
    6
    7
    Haemoptysis
         subjects affected / exposed
    3 / 51 (5.88%)
    5 / 48 (10.42%)
         occurrences all number
    3
    8
    Oropharyngeal pain
         subjects affected / exposed
    2 / 51 (3.92%)
    5 / 48 (10.42%)
         occurrences all number
    2
    6
    Sputum increased
         subjects affected / exposed
    2 / 51 (3.92%)
    4 / 48 (8.33%)
         occurrences all number
    2
    5
    Wheezing
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    3
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    4
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 51 (3.92%)
    3 / 48 (6.25%)
         occurrences all number
    2
    3
    Arthralgia
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 48 (0.00%)
         occurrences all number
    5
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    5 / 51 (9.80%)
    6 / 48 (12.50%)
         occurrences all number
    5
    6
    Nasopharyngitis
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 48 (0.00%)
         occurrences all number
    3
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    0
    4
    Urinary tract infection
         subjects affected / exposed
    3 / 51 (5.88%)
    2 / 48 (4.17%)
         occurrences all number
    3
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 51 (3.92%)
    5 / 48 (10.42%)
         occurrences all number
    2
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Aug 2021
    The following changes were made as per Amendment 01 - 1. AZI+ETH were moved to background regimen. 2. Updated objectives and endpoints 1, 2, 3, 4, 5, 6, and 9. 3. Updated inclusion and exclusion criteria.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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