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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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 Avi

Conditions
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Mycobacterium Infections, Nontuberculous

Intervention / Treatment
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* Drug: ALIS
* Drug: Azithromycin
* Drug: Ethambutol
* Drug: ELC


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ALIS + Background Regimen (Azithromycin + Ethambutol)<br>Participants will be administered 590 mg of ALIS (amikacin liposome inhalation suspension) once daily. Participants will also be administered the background regimen of azithromycin 250 mg and ethambutol 15 mg/kg tablets orally, once daily. | Drug: ALIS<br>* Inhalation via nebulization over approximately 6 to 15 minutes.<br>* Other names: ARIKAYCE®;Drug: Azithromycin<br>* Oral tablet<br>* Other names: AZI;Drug: Ethambutol<br>* Oral tablet<br>* Other names: ETH;|
| Placebo Comparator: ELC + Background Regimen (Azithromycin + Ethambutol)<br>Participants will be administered ELC (empty liposome control), a matching placebo to ALIS, once daily. Participants will also be administered the background regimen of azithromycin 250 mg and ethambutol 15 mg/kg tablets orally, once daily. | Drug: Azithromycin<br>* Oral tablet<br>* Other names: AZI;Drug: Ethambutol<br>* Oral tablet<br>* Other names: ETH;Drug: ELC<br>* Inhalation via nebulization over approximately 6 to 15 minutes.<br>* Other names: Empty liposome control;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Psychometric Cross-Sectional Validation of Patient Reported Outcome (PRO): Patient Global Impression of Severity (PGI-S) |  | Baseline | 
| Psychometric Cross-Sectional Validation of PRO: Quality of Life Questionnaire - Bronchiectasis (QoL-B) |  | Baseline | 
| Psychometric Cross-Sectional Validation of PRO: Patient-Reported Outcome Measurement Information System - Fatigue-Short Form 7a (PROMIS F-SF 7a) |  | Baseline | 
| Assessment of Test-Retest Reliability Reported as the Estimate of Score Among Participants Reporting no Change on Respiratory PGI-S Applied to QOL-B Respiratory Domain Between Screening and Baseline |  | Screening (Day -70 to Day 1) and Baseline | 
| Assessment of Test-Retest Reliability Reported as the Estimate of Score Among Participants Reporting no Change on Fatigue PGI-S Applied to PROMIS F-SF 7a Between Screening and Baseline |  | Screening (Day -70 to Day 1) and Baseline | 
| Response Rate as Assessed by Within-Participant Meaningful Change Estimated via Anchor-Based Methods and Validated via Empirical Cumulative Distribution Functions (eCDFs) |  | Baseline to Month 7 | 
| Response Rate as Assessed by Within-Participant Meaningful Change Estimated via Anchor-Based Methods and Validated via Empirical Probability Density Functions (ePDFs) |  | Baseline to Month 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Culture Conversion by Month 6 |  | Month 6 | 
| Change from Baseline in Respiratory Symptom Score at Month 7 |  | Baseline to Month 7 | 
| Change from Baseline in Fatigue Symptom Score at Month 7 |  | Baseline to Month 7 | 
| Time to Culture Conversion |  | Baseline to Month 6 | 
| Time to First Negative Culture |  | Baseline to Month 6 | 
| Percentage of Participants Who Develop a Mycobacterium avium Complex (MAC) Isolate With Amikacin Minimum Inhibitory Concentration (MIC) ≥ 128 micrograms per millliliter (µg/mL) at More Than 1 Visit |  | Up to Month 7 | 
| Percentage of Participants Achieving Culture Conversion and a Subsequent at Least one MAC Positive Culture in Agar Media or Broth Media in at Least 2 Consecutive Visits With Matching Species and Genome at Screening/ Baseline |  | Baseline to Month 7 | 
| Percentage of Participants Achieving Culture Conversion and a Subsequently have at least One MAC Positive Culture in Agar Media or Broth Media in at Least 2 Consecutive Visits With Differing Species and/or Genome at Screening/ Baseline |  | Baseline to Month 7 | 
| Number of Participants Who Experience an Adverse Event (AEs) |  | Baseline to Month 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nontuberculous Mycobacterial Lung Infection, Mycobacterium avium complex, Psychometric validation, Patient-reported outcome