Trial Outcomes & Findings for Validation of Patient Reported Outcome Measures in Participants With Nontuberculous Mycobacterial Lung Infection Caused by Mycobacterium Avium Complex (NCT NCT04677543)

Last Updated: 2024-06-28

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

99 participants

Primary outcome timeframe

Baseline

Results posted on

2024-06-28

Participant Flow

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

Participant milestones

Participant milestones
Measure	ALIS + Background Regimen (Azithromycin + Ethambutol) 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.	ELC + Background Regimen (Azithromycin + Ethambutol) 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.
Overall Study STARTED	48	51
Overall Study COMPLETED	44	48
Overall Study NOT COMPLETED	4	3

Reasons for withdrawal

Reasons for withdrawal
Measure	ALIS + Background Regimen (Azithromycin + Ethambutol) 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.	ELC + Background Regimen (Azithromycin + Ethambutol) 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.
Overall Study Withdrawal by Subject	4	1
Overall Study Physician Decision	0	1
Overall Study Adverse Event	0	1

Baseline Characteristics

Validation of Patient Reported Outcome Measures in Participants With Nontuberculous Mycobacterial Lung Infection Caused by Mycobacterium Avium Complex

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	ALIS + Background Regimen (Azithromycin + Ethambutol) n=48 Participants 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.	ELC + Background Regimen (Azithromycin + Ethambutol) n=51 Participants 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.	Total n=99 Participants Total of all reporting groups
Age, Continuous	69.0 Years STANDARD_DEVIATION 9.51 • n=5 Participants	65.9 Years STANDARD_DEVIATION 12.27 • n=7 Participants	67.4 Years STANDARD_DEVIATION 11.07 • n=5 Participants
Sex: Female, Male Female	32 Participants n=5 Participants	45 Participants n=7 Participants	77 Participants n=5 Participants
Sex: Female, Male Male	16 Participants n=5 Participants	6 Participants n=7 Participants	22 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	45 Participants n=5 Participants	48 Participants n=7 Participants	93 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	6 Participants n=5 Participants	12 Participants n=7 Participants	18 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) White	41 Participants n=5 Participants	39 Participants n=7 Participants	80 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline

Population: ITT Analysis Set comprises all participants who were randomized.

Outcome measures

Outcome measures
Measure	ALIS + Background Regimen (Azithromycin + Ethambutol) n=48 Participants 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.	ELC + Background Regimen (Azithromycin + Ethambutol) n=51 Participants 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.
Psychometric Cross-Sectional Validation of Patient Reported Outcome (PRO): Patient Global Impression of Severity (PGI-S) Respiratory Scale Score at Baseline	2.5 score on scale Standard Deviation 0.82	2.4 score on scale Standard Deviation 0.90

PRIMARY outcome

Timeframe: Baseline

Population: ITT Analysis Set comprises all participants who were randomized.

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.

Outcome measures

Outcome measures
Measure	ALIS + Background Regimen (Azithromycin + Ethambutol) n=48 Participants 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.	ELC + Background Regimen (Azithromycin + Ethambutol) n=51 Participants 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.
Psychometric Cross-Sectional Validation of PRO: PGI-S Fatigue Scale Score at Baseline	2.5 score on scale Standard Deviation 0.99	2.5 score on scale Standard Deviation 0.81

PRIMARY outcome

Timeframe: Baseline

Population: The ITT Analysis Set comprises all participants who were randomized.

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.

Outcome measures

Outcome measures
Measure	ALIS + Background Regimen (Azithromycin + Ethambutol) n=48 Participants 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.	ELC + Background Regimen (Azithromycin + Ethambutol) n=51 Participants 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.
Psychometric Cross-Sectional Validation of PRO: Quality of Life Questionnaire - Bronchiectasis (QoL-B) Respiratory Symptoms Scale Score at Baseline	63.04 score on scale Standard Deviation 14.824	66.90 score on scale Standard Deviation 15.673

PRIMARY outcome

Timeframe: Baseline

Population: The ITT Analysis Set comprises all participants who were randomized.

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.

Outcome measures

Outcome measures
Measure	ALIS + Background Regimen (Azithromycin + Ethambutol) n=48 Participants 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.	ELC + Background Regimen (Azithromycin + Ethambutol) n=51 Participants 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.
Psychometric Cross-Sectional Validation of PRO: Patient-Reported Outcome Measurement Information System - Fatigue-Short Form 7a (PROMIS F-SF 7a) Score at Baseline	18.3 score on scale Standard Deviation 5.76	18.6 score on scale Standard Deviation 4.76

PRIMARY outcome

Timeframe: From Screening to Baseline (Day -70 to Day 1)

Population: As pre-specified in the SAP, to adequately power the planned modern psychometric methods (MPMs) the cross-sectional validation sample was composed of a total of 97 participants enrolled in the INS-415 study (comprising of pooled ALIS + ELC data per planned analyses) who provided item-level QOL-B Respiratory domain data and Screening/Baseline data from the first 132 participants enrolled in the INS-416 study (NCT04677569) to yield a total sample of n=229.

TRTR consists of measuring the 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 the two-way mixed effect ICC coefficient estimated using the inter-rater reliability package, version 0.84.1. TRTR estimate of 0.7 and above indicated better retest reliability. TRTR was assessed among participants reporting no change on PGI-S between screening and baseline. PGI-S anchors are PRO specific, with a respiratory PGI-S (scale ranging from 1=not at all to 5=extremely severe, Higher scores=greater symptom severity) applied to the 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 statistical analysis plan(SAP) for participants contributing to this outcome measure from INS-415 study,data were collected and analyzed for combined population in which ALIS and ELC groups were pooled.

Outcome measures

Outcome measures
Measure	ALIS + Background Regimen (Azithromycin + Ethambutol) n=229 Participants 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.	ELC + Background Regimen (Azithromycin + Ethambutol) 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.
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	0.69 ICC estimate	—

PRIMARY outcome

Timeframe: From Screening to Baseline (Day -70 to Day 1)

Population: As pre-specified in the SAP, to adequately power the planned MPMs the cross-sectional validation sample was composed of a total of 98 participants enrolled in the INS-415 study (comprising of pooled ALIS + ELC data per planned analyses) who provided item-level PROMIS F-SF 7a data and Screening/Baseline data from the first 132 participants enrolled in the INS-416 study to yield a total sample of n=230.

TRTR consists of measuring the 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 the two-way mixed effect ICC coefficient estimated using the 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 the SAP, for participants contributing to this outcome measure from INS-415 study, data were collected and analyzed for combined population in which ALIS and ELC groups were pooled.

Outcome measures

Outcome measures
Measure	ALIS + Background Regimen (Azithromycin + Ethambutol) n=230 Participants 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.	ELC + Background Regimen (Azithromycin + Ethambutol) 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.
Assessment of TRTR Reported as the ICC Estimate Among Participants Reporting no Change on Fatigue PGI-S Score Applied to PROMIS F-SF 7a Score Between Screening and Baseline	0.76 ICC estimate	—

PRIMARY outcome

Timeframe: Baseline to Month 7

Population: The ITT Analysis Set comprises all participants who were randomized.

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.

Outcome measures

Outcome measures
Measure	ALIS + Background Regimen (Azithromycin + Ethambutol) n=48 Participants 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.	ELC + Background Regimen (Azithromycin + Ethambutol) n=51 Participants 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.
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)	43.8 percentage of participants Interval 29.8 to 57.8	33.3 percentage of participants Interval 20.4 to 46.2

PRIMARY outcome

Timeframe: Baseline to Month 7

Population: The ITT Analysis Set comprises all participants who were randomized.

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.

Outcome measures

Outcome measures
Measure	ALIS + Background Regimen (Azithromycin + Ethambutol) n=48 Participants 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.	ELC + Background Regimen (Azithromycin + Ethambutol) n=51 Participants 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.
Response Rate as Assessed by WSMC for PROMIS Fatigue Final Score Estimated Via Anchor-Based Methods and Validated Via eCDFs	35.5 percentage of participants Interval 22.2 to 48.7	29.4 percentage of participants Interval 17.1 to 41.6

SECONDARY outcome

Timeframe: Baseline to Month 6

Population: The ITT Analysis Set comprises all participants who were randomized.

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.

Outcome measures

Outcome measures
Measure	ALIS + Background Regimen (Azithromycin + Ethambutol) n=48 Participants 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.	ELC + Background Regimen (Azithromycin + Ethambutol) n=51 Participants 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.
Percentage of Participants Achieving Culture Conversion by Month 6	80.6 percentage of participants Interval 68.7 to 92.6	63.9 percentage of participants Interval 50.2 to 77.6

SECONDARY outcome

Timeframe: Baseline to Month 7

Population: The ITT Analysis Set comprises all participants who were randomized.

Outcome measures

Outcome measures
Measure	ALIS + Background Regimen (Azithromycin + Ethambutol) n=48 Participants 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.	ELC + Background Regimen (Azithromycin + Ethambutol) n=51 Participants 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.
Change From Baseline in QOL-B Respiratory Symptom Score at Month 7	12.24 score on scale Interval 7.96 to 16.53	7.76 score on scale Interval 3.76 to 11.77

SECONDARY outcome

Timeframe: Baseline to Month 7

Population: The ITT Analysis Set comprises all participants who were randomized.

Outcome measures

Outcome measures
Measure	ALIS + Background Regimen (Azithromycin + Ethambutol) n=48 Participants 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.	ELC + Background Regimen (Azithromycin + Ethambutol) n=51 Participants 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.
Change From Baseline in PROMIS F-SF 7a Score at Month 7	-2.1 score on a scale Interval -3.4 to -0.8	-1.6 score on a scale Interval -2.9 to -0.3

SECONDARY outcome

Timeframe: Baseline to Month 6

Population: The ITT Analysis Set comprises all participants who were randomized. Overall number analyzed is the number of participants with culture conversion who had data available for analyses.

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.

Outcome measures

Outcome measures
Measure	ALIS + Background Regimen (Azithromycin + Ethambutol) n=39 Participants 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.	ELC + Background Regimen (Azithromycin + Ethambutol) n=40 Participants 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.
Time to First Culture Conversion	1.0 months Interval 1.0 to 5.0	2.0 months Interval 1.0 to 5.0

SECONDARY outcome

Timeframe: Baseline to Month 7

Population: The ITT Analysis Set comprises all participants who were randomized. Overall number analyzed is the number of participants with a negative culture.

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.

Outcome measures

Outcome measures
Measure	ALIS + Background Regimen (Azithromycin + Ethambutol) n=45 Participants 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.	ELC + Background Regimen (Azithromycin + Ethambutol) n=44 Participants 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.
Time to First Negative Culture	1.0 months Interval 1.0 to 3.0	1.0 months Interval 1.0 to 7.0

SECONDARY outcome

Timeframe: Up to Month 7

Population: The ITT Analysis Set comprises all participants who were randomized.

Outcome measures

Outcome measures
Measure	ALIS + Background Regimen (Azithromycin + Ethambutol) n=48 Participants 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.	ELC + Background Regimen (Azithromycin + Ethambutol) n=51 Participants 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.
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	0 percentage of participants	0 percentage of participants

SECONDARY outcome

Timeframe: Baseline to Month 7

Population: The ITT Analysis Set comprises all participants who were randomized. Overall number analyzed is the number of participants who had conversion before or at Month 5 with data available for analyses.

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.

Outcome measures

Outcome measures
Measure	ALIS + Background Regimen (Azithromycin + Ethambutol) n=39 Participants 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.	ELC + Background Regimen (Azithromycin + Ethambutol) n=40 Participants 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.
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	5.1 percentage of participants	22.5 percentage of participants

SECONDARY outcome

Timeframe: Baseline to Month 7

Outcome measures

Outcome measures
Measure	ALIS + Background Regimen (Azithromycin + Ethambutol) n=39 Participants 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.	ELC + Background Regimen (Azithromycin + Ethambutol) n=40 Participants 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.
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	5.1 percentage of participants	25.0 percentage of participants

SECONDARY outcome

Timeframe: Baseline to Month 7

Population: The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.

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.

Outcome measures

Outcome measures
Measure	ALIS + Background Regimen (Azithromycin + Ethambutol) n=48 Participants 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.	ELC + Background Regimen (Azithromycin + Ethambutol) n=51 Participants 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.
Number of Participants Who Experience Any Treatment-emergent Adverse Event (TEAE)	44 Participants	41 Participants

Adverse Events

ALIS + Background Regimen (Azithromycin + Ethambutol)

Serious events: 7 serious events

Other events: 38 other events

Deaths: 0 deaths

ELC + Background Regimen (Azithromycin + Ethambutol)

Serious events: 3 serious events

Other events: 33 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Insmed Medical Information

Insmed Incorporated

Phone: 1-844-446-7633

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	ALIS + Background Regimen (Azithromycin + Ethambutol) n=48 participants at risk 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.	ELC + Background Regimen (Azithromycin + Ethambutol) n=51 participants at risk 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.
Infections and infestations Bronchiolitis	2.1% 1/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	0.00% 0/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Infections and infestations Infective exacerbation of bronchiectasis	0.00% 0/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	2.0% 1/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Infections and infestations Rhinovirus infection	0.00% 0/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	2.0% 1/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Cardiac disorders Acute coronary syndrome	2.1% 1/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	0.00% 0/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Cardiac disorders Atrial fibrillation	0.00% 0/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	2.0% 1/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Cardiac disorders Cardiac failure chronic	0.00% 0/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	2.0% 1/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Nervous system disorders Aphasia	2.1% 1/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	0.00% 0/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Nervous system disorders Carotid artery stenosis	2.1% 1/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	0.00% 0/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	2.0% 1/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Respiratory, thoracic and mediastinal disorders Haemoptysis	0.00% 0/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	2.0% 1/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
General disorders Oedema peripheral	0.00% 0/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	2.0% 1/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Immune system disorders Drug hypersensitivity	2.1% 1/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	0.00% 0/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Injury, poisoning and procedural complications Femoral neck fracture	2.1% 1/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	0.00% 0/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Investigations Ejection fraction decreased	0.00% 0/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	2.0% 1/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of skin	2.1% 1/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	0.00% 0/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.

Measure	ALIS + Background Regimen (Azithromycin + Ethambutol) n=48 participants at risk 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.	ELC + Background Regimen (Azithromycin + Ethambutol) n=51 participants at risk 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.
Ear and labyrinth disorders Tinnitus	4.2% 2/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	7.8% 4/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Eye disorders Vision blurred	0.00% 0/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	5.9% 3/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Gastrointestinal disorders Diarrhoea	27.1% 13/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	25.5% 13/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Gastrointestinal disorders Nausea	10.4% 5/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	7.8% 4/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Gastrointestinal disorders Abdominal pain	8.3% 4/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	7.8% 4/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Gastrointestinal disorders Abdominal pain upper	8.3% 4/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	2.0% 1/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
General disorders Fatigue	10.4% 5/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	11.8% 6/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
General disorders Asthenia	4.2% 2/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	9.8% 5/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Infections and infestations COVID-19	12.5% 6/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	9.8% 5/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Infections and infestations Urinary tract infection	4.2% 2/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	5.9% 3/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Infections and infestations Upper respiratory tract infection	6.2% 3/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	0.00% 0/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Infections and infestations Nasopharyngitis	0.00% 0/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	5.9% 3/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Investigations Weight decreased	8.3% 4/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	0.00% 0/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Metabolism and nutrition disorders Decreased appetite	10.4% 5/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	3.9% 2/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	5.9% 3/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Musculoskeletal and connective tissue disorders Back pain	6.2% 3/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	3.9% 2/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Nervous system disorders Headache	10.4% 5/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	11.8% 6/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Nervous system disorders Dizziness	4.2% 2/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	9.8% 5/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Respiratory, thoracic and mediastinal disorders Dysphonia	41.7% 20/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	3.9% 2/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Respiratory, thoracic and mediastinal disorders Cough	27.1% 13/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	7.8% 4/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Respiratory, thoracic and mediastinal disorders Dyspnoea	10.4% 5/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	7.8% 4/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Respiratory, thoracic and mediastinal disorders Haemoptysis	10.4% 5/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	5.9% 3/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	10.4% 5/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	3.9% 2/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Respiratory, thoracic and mediastinal disorders Sputum increased	8.3% 4/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	3.9% 2/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Respiratory, thoracic and mediastinal disorders Wheezing	6.2% 3/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	0.00% 0/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.
Skin and subcutaneous tissue disorders Rash	6.2% 3/48 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.	0.00% 0/51 • Baseline to Month 7 The Safety Analysis Set comprises all participants who were randomized and received at least 1 dose of ALIS, ELC, azithromycin or ethambutol.