Mycobacterium Infections, Nontuberculous
Conditions
Keywords
Nontuberculous Mycobacterial Lung Infection, Mycobacterium avium complex, Psychometric validation, Patient-reported outcome
Brief summary
The primary objective of this study is 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.
Detailed description
Participants will also complete the EXAcerbations of Chronic Pulmonary Disease Tool (EXACT), EXACT Respiratory Symptoms (EXACT-RS), St. George Respiratory Questionnaire (SGRQ), Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue), Patient Global Impression of Severity - Respiratory (PGIS-Respiratory), and Patient Global Impression of Severity - Fatigue (PGIS-Fatigue) at baseline and throughout the study as anchors for the validation of the QoL-B and PROMIS F-SF 7a.
Interventions
DRUGALIS
Inhalation via nebulization over approximately 6 to 15 minutes.
DRUGAzithromycin
Oral tablet
DRUGEthambutol
Oral tablet
DRUGELC
Inhalation via nebulization over approximately 6 to 15 minutes.
Sponsors
Insmed Incorporated
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female, ≥ 18 years of age (19 years or older in South Korea) * Current diagnosis of Mycobacterium avium Complex (MAC) lung infection * Positive sputum culture for MAC within 6 months prior to screening * A chest computed tomography (CT) scan, read locally, within 6 months prior to Screening to determine presence and size of pulmonary cavities. Participants who do not have a chest CT scan within 6 months prior to Screening will be required to obtain a chest CT scan, read locally, during Screening * Willingness and ability to adhere to prescribed study treatment during the study * Ability to produce (spontaneously or with induction) approximately 2 mL of sputum for mycobacteriology at Screening * Women of child-bearing potential (WOCBP) (ie, fertile following menarche and until becoming post-menopausal unless permanently sterile) and fertile men (ie, all men after puberty unless permanently sterile by bilateral orchidectomy) agree to practice a highly effective method of birth control from Day 1 to at least 90 days after the last dose. Examples of such birth controls are: * true abstinence (refraining from heterosexual intercourse during the entire study), * copper intrauterine device (IUD), * hormonal methods (levonorgestrel-releasing intrauterine system, progestogen implant, combined oral contraceptive pill \[combined with barrier method\]), * exclusive homosexual relationship, or * sole male partner who has undergone surgical sterilization with confirmation of azoospermia at least 3 months post procedure while participating in the study * Provide signed informed consent prior to administration of study drugs or performing any study related procedure * Be able to comply with study drugs use, study visits, and study procedures as defined by the protocol * Men with partners who are WOCBP (pregnant or non-pregnant) agree to use condoms and non-pregnant partners should practice a highly effective method of birth control
Exclusion criteria
* Diagnosis of cystic fibrosis (CF) * History of more than 3 MAC lung infections * Received any mycobacterial antibiotic treatment for current MAC lung infection * Refractory MAC lung infection, defined as having positive MAC cultures while being treated with a multidrug mycobacterial antibiotic treatment regimen for a minimum of 6 consecutive months and no documented successful treatment, defined as negative sputum culture for MAC and cessation of treatment * Relapse of prior MAC lung infection, defined as positive sputum culture for MAC ≤ 6 months of cessation of prior successful treatment * Evidence of any pulmonary cavity ≥ 2 cm in diameter, as determined by chest CT scan, read locally, within 6 months prior to Screening * Radiographic finding of new lobar consolidation, atelectasis, significant pleural effusion, or pneumothorax during routine clinical care within 2 months prior to Screening * Active pulmonary malignancy (primary or metastatic) or any malignancy requiring chemotherapy or radiation therapy within 1 year prior to Screening or anticipated during the study * Acute pulmonary exacerbation (eg, chronic obstructive pulmonary disease \[COPD\] or bronchiectasis) requiring treatment with antibiotics, or corticosteroids (intravenous \[IV\] or oral), within 4 weeks prior to and during Screening * Current smoker * History of lung transplantation * Prior exposure to amikacin liposome inhalation suspension (ALIS) (including clinical study) * Known hypersensitivity or contraindications to use to ALIS, aminoglycosides, or any of their excipients * Disseminated MAC infection * Positive pregnancy test or lactation at Screening. All WOCBP will be tested. Women not of childbearing potential are defined as postmenopausal (ie, amenorrheic for 12 months without an alternative medical cause or confirmed by more than one follicle stimulating hormone \[FSH\] measurement), or naturally or surgically sterile through bilateral oophorectomy, hysterectomy, or bilateral salpingectomy. For women under the age of 45 years, confirmatory testing with FSH should be considered * Administration of any investigational drug within 8 weeks prior to Screening * Known or suspected acquired immunodeficiency syndromes (HIV-positive, regardless of CD4 counts). Other immunodeficiency syndromes that may interfere with study participation in the opinion of the Investigator. * Current alcohol, medication, or illicit drug abuse * Known and active COVID-19 infection * MAC isolate with MIC for clarithromycin ≥ 32 µg/mL at Screening * Known hypersensitivity or contraindications to use to ethambutol, azithromycin (including other macrolides or ketolides), or any of their excipients per local labeling guidance.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Psychometric Cross-Sectional Validation of Patient Reported Outcome (PRO): Patient Global Impression of Severity (PGI-S) Respiratory Scale Score at Baseline | Baseline | 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. |
| Psychometric Cross-Sectional Validation of PRO: PGI-S Fatigue Scale Score at Baseline | Baseline | 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. |
| Psychometric Cross-Sectional Validation of PRO: Quality of Life Questionnaire - Bronchiectasis (QoL-B) Respiratory Symptoms Scale Score at Baseline | Baseline | 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. |
| Psychometric Cross-Sectional Validation of PRO: Patient-Reported Outcome Measurement Information System - Fatigue-Short Form 7a (PROMIS F-SF 7a) Score at Baseline | Baseline | 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. |
| 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 | From Screening to Baseline (Day -70 to Day 1) | 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. |
| 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 | From Screening to Baseline (Day -70 to Day 1) | 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. |
| 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) | Baseline to Month 7 | 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. |
| Response Rate as Assessed by WSMC for PROMIS Fatigue Final Score Estimated Via Anchor-Based Methods and Validated Via eCDFs | Baseline to Month 7 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving Culture Conversion by Month 6 | Baseline to Month 6 | 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. |
| Change From Baseline in QOL-B Respiratory Symptom Score at Month 7 | Baseline to Month 7 | 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. Positive change from baseline indicates improvement. |
| Change From Baseline in PROMIS F-SF 7a Score at Month 7 | Baseline to Month 7 | 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. |
| Time to First Culture Conversion | Baseline to Month 6 | 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. |
| Time to First Negative Culture | Baseline to Month 7 | 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. |
| 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 | Up to Month 7 | — |
| 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 | Baseline to Month 7 | 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. |
| 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 | Baseline to Month 7 | 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. |
| Number of Participants Who Experience Any Treatment-emergent Adverse Event (TEAE) | Baseline to Month 7 | 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. |
Countries
Argentina, Australia, Austria, Denmark, Germany, Israel, Italy, New Zealand, South Korea, Spain, Taiwan, United States
Participant flow
Recruitment details
Participants took part in this multi-centre study at different investigative sites from 22 December 2020 to 09 May 2023
Participants by arm
| Arm | Count |
|---|---|
| ALIS + Background Regimen (Azithromycin + Ethambutol) 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. | 48 |
| 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. | 51 |
| Total | 99 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 1 |
Baseline characteristics
| Characteristic | ELC + Background Regimen (Azithromycin + Ethambutol) | Total | ALIS + Background Regimen (Azithromycin + Ethambutol) |
|---|---|---|---|
| Age, Continuous | 65.9 Years STANDARD_DEVIATION 12.27 | 67.4 Years STANDARD_DEVIATION 11.07 | 69.0 Years STANDARD_DEVIATION 9.51 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 6 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 48 Participants | 93 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 12 Participants | 18 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 39 Participants | 80 Participants | 41 Participants |
| Sex: Female, Male Female | 45 Participants | 77 Participants | 32 Participants |
| Sex: Female, Male Male | 6 Participants | 22 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 48 | 0 / 51 |
| other Total, other adverse events | 38 / 48 | 33 / 51 |
| serious Total, serious adverse events | 7 / 48 | 3 / 51 |
Outcome results
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
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ALIS + Background Regimen (Azithromycin + Ethambutol) | 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
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
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ALIS + Background Regimen (Azithromycin + Ethambutol) | 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
Psychometric Cross-Sectional Validation of Patient Reported Outcome (PRO): Patient Global Impression of Severity (PGI-S) Respiratory Scale Score at Baseline
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.
Time frame: Baseline
Population: ITT Analysis Set comprises all participants who were randomized.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ALIS + Background Regimen (Azithromycin + Ethambutol) | 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 |
| ELC + Background Regimen (Azithromycin + Ethambutol) | Psychometric Cross-Sectional Validation of Patient Reported Outcome (PRO): Patient Global Impression of Severity (PGI-S) Respiratory Scale Score at Baseline | 2.4 score on scale | Standard Deviation 0.9 |
Primary
Psychometric Cross-Sectional Validation of PRO: Patient-Reported Outcome Measurement Information System - Fatigue-Short Form 7a (PROMIS F-SF 7a) Score at Baseline
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.
Time frame: Baseline
Population: The ITT Analysis Set comprises all participants who were randomized.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ALIS + Background Regimen (Azithromycin + Ethambutol) | 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 |
| ELC + Background Regimen (Azithromycin + Ethambutol) | Psychometric Cross-Sectional Validation of PRO: Patient-Reported Outcome Measurement Information System - Fatigue-Short Form 7a (PROMIS F-SF 7a) Score at Baseline | 18.6 score on scale | Standard Deviation 4.76 |
Primary
Psychometric Cross-Sectional Validation of PRO: PGI-S Fatigue Scale Score at Baseline
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.
Time frame: Baseline
Population: ITT Analysis Set comprises all participants who were randomized.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ALIS + Background Regimen (Azithromycin + Ethambutol) | Psychometric Cross-Sectional Validation of PRO: PGI-S Fatigue Scale Score at Baseline | 2.5 score on scale | Standard Deviation 0.99 |
| ELC + Background Regimen (Azithromycin + Ethambutol) | Psychometric Cross-Sectional Validation of PRO: PGI-S Fatigue Scale Score at Baseline | 2.5 score on scale | Standard Deviation 0.81 |
Primary
Psychometric Cross-Sectional Validation of PRO: Quality of Life Questionnaire - Bronchiectasis (QoL-B) Respiratory Symptoms Scale Score at Baseline
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.
Time frame: Baseline
Population: The ITT Analysis Set comprises all participants who were randomized.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ALIS + Background Regimen (Azithromycin + Ethambutol) | 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 |
| ELC + Background Regimen (Azithromycin + Ethambutol) | Psychometric Cross-Sectional Validation of PRO: Quality of Life Questionnaire - Bronchiectasis (QoL-B) Respiratory Symptoms Scale Score at Baseline | 66.90 score on scale | Standard Deviation 15.673 |
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)
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.
Time frame: Baseline to Month 7
Population: The ITT Analysis Set comprises all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ALIS + Background Regimen (Azithromycin + Ethambutol) | 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 |
| ELC + Background Regimen (Azithromycin + Ethambutol) | 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) | 33.3 percentage of participants |
p-value: 0.281995% CI: [-8.6, 29.5]Standardized Logistic Regression
Primary
Response Rate as Assessed by WSMC for PROMIS Fatigue Final Score Estimated Via Anchor-Based Methods and Validated Via eCDFs
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.
Time frame: Baseline to Month 7
Population: The ITT Analysis Set comprises all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ALIS + Background Regimen (Azithromycin + Ethambutol) | 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 |
| ELC + Background Regimen (Azithromycin + Ethambutol) | Response Rate as Assessed by WSMC for PROMIS Fatigue Final Score Estimated Via Anchor-Based Methods and Validated Via eCDFs | 29.4 percentage of participants |
p-value: 0.50895% CI: [-11.9, 24.1]Standardized Logistic Regression
Secondary
Change From Baseline in PROMIS F-SF 7a Score at Month 7
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.
Time frame: Baseline to Month 7
Population: The ITT Analysis Set comprises all participants who were randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ALIS + Background Regimen (Azithromycin + Ethambutol) | Change From Baseline in PROMIS F-SF 7a Score at Month 7 | -2.1 score on a scale |
| ELC + Background Regimen (Azithromycin + Ethambutol) | Change From Baseline in PROMIS F-SF 7a Score at Month 7 | -1.6 score on a scale |
p-value: 0.61395% CI: [-2.2, 1.3]ANCOVA
Secondary
Change From Baseline in QOL-B Respiratory Symptom Score at Month 7
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. Positive change from baseline indicates improvement.
Time frame: Baseline to Month 7
Population: The ITT Analysis Set comprises all participants who were randomized.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| ALIS + Background Regimen (Azithromycin + Ethambutol) | Change From Baseline in QOL-B Respiratory Symptom Score at Month 7 | 12.24 score on scale |
| ELC + Background Regimen (Azithromycin + Ethambutol) | Change From Baseline in QOL-B Respiratory Symptom Score at Month 7 | 7.76 score on scale |
p-value: 0.107395% CI: [-0.97, 9.93]ANCOVA
Secondary
Number of Participants Who Experience Any Treatment-emergent Adverse Event (TEAE)
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.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| ALIS + Background Regimen (Azithromycin + Ethambutol) | Number of Participants Who Experience Any Treatment-emergent Adverse Event (TEAE) | 44 Participants |
| ELC + Background Regimen (Azithromycin + Ethambutol) | Number of Participants Who Experience Any Treatment-emergent Adverse Event (TEAE) | 41 Participants |
Secondary
Percentage of Participants Achieving Culture Conversion by Month 6
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.
Time frame: Baseline to Month 6
Population: The ITT Analysis Set comprises all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ALIS + Background Regimen (Azithromycin + Ethambutol) | Percentage of Participants Achieving Culture Conversion by Month 6 | 80.6 percentage of participants |
| ELC + Background Regimen (Azithromycin + Ethambutol) | Percentage of Participants Achieving Culture Conversion by Month 6 | 63.9 percentage of participants |
p-value: 0.071295% CI: [-1.4, 34.9]Standardized Logistic Regression
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
Time frame: Up to Month 7
Population: The ITT Analysis Set comprises all participants who were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ALIS + Background Regimen (Azithromycin + Ethambutol) | 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 |
| ELC + Background Regimen (Azithromycin + Ethambutol) | 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 |
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
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ALIS + Background Regimen (Azithromycin + Ethambutol) | 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 |
| ELC + Background Regimen (Azithromycin + Ethambutol) | 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 | 25.0 percentage of participants |
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
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ALIS + Background Regimen (Azithromycin + Ethambutol) | 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 |
| ELC + Background Regimen (Azithromycin + Ethambutol) | 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 | 22.5 percentage of participants |
Secondary
Time to First Culture Conversion
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ALIS + Background Regimen (Azithromycin + Ethambutol) | Time to First Culture Conversion | 1.0 months |
| ELC + Background Regimen (Azithromycin + Ethambutol) | Time to First Culture Conversion | 2.0 months |
p-value: 0.354295% CI: [0.79, 1.92]Regression, Cox
Secondary
Time to First 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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ALIS + Background Regimen (Azithromycin + Ethambutol) | Time to First Negative Culture | 1.0 months |
| ELC + Background Regimen (Azithromycin + Ethambutol) | Time to First Negative Culture | 1.0 months |
p-value: 0.158395% CI: [0.89, 2.06]Regression, Cox