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

NCT04677543 | Completed Phase 3 Results DMC FDA Drug

• 2 other identifiers: INS-4152020-002545-42
• Study Type: interventional
• Target: 99
• Locations: 11 countries
• Sites: 59

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.

Conditions

Mycobacterium Infections, Nontuberculous

Keywords

Nontuberculous Mycobacterial Lung Infection; Mycobacterium avium complex; Psychometric validation; Patient-reported outcome

Outcome Measures

Primary Outcomes (8)

• 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.

  Baseline

• 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.

  Baseline

• 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.

  Baseline

• 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.

  Baseline

• 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.

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

• 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.

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

• 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.

  Baseline to Month 7

• 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.

  Baseline to Month 7

Secondary Outcomes (9)

• Percentage of Participants Achieving Culture Conversion by Month 6

  Baseline to Month 6

• Change From Baseline in QOL-B Respiratory Symptom Score at Month 7

  Baseline to Month 7

• Change From Baseline in PROMIS F-SF 7a Score at Month 7

  Baseline to Month 7

• Time to First Culture Conversion

  Baseline to Month 6

• Time to First Negative Culture

  Baseline to Month 7

Study Arms (2)

ALIS + Background Regimen (Azithromycin + Ethambutol)

ACTIVE COMPARATOR

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; Drug: Azithromycin; Drug: Ethambutol

ELC + Background Regimen (Azithromycin + Ethambutol)

PLACEBO COMPARATOR

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; Drug: Ethambutol; Drug: ELC

Interventions

ALIS DRUG

Inhalation via nebulization over approximately 6 to 15 minutes.

Also known as: Amikacin liposome inhalation suspension, ARIKAYCE®

ALIS + Background Regimen (Azithromycin + Ethambutol)

Azithromycin DRUG

Oral tablet

Also known as: AZI

ALIS + Background Regimen (Azithromycin + Ethambutol); ELC + Background Regimen (Azithromycin + Ethambutol)

Ethambutol DRUG

Oral tablet

Also known as: ETH

ALIS + Background Regimen (Azithromycin + Ethambutol); ELC + Background Regimen (Azithromycin + Ethambutol)

ELC DRUG

Inhalation via nebulization over approximately 6 to 15 minutes.

Also known as: Empty liposome control

ELC + Background Regimen (Azithromycin + Ethambutol)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Insmed Incorporated: lead

Study Sites (62)

USA008

Birmingham, Alabama, 35233-1711, United States

Location

USA062

Fresno, California, 93701-2302, United States

Location

USA048

San Diego, California, 92121-3018, United States

Location

USA050

Stanford, California, 94305, United States

Location

USA023

Washington D.C., District of Columbia, 20007, United States

Location

USA003

Clearwater, Florida, 33765, United States

Location

USA072

Jacksonville, Florida, 32207-8567, United States

Location

USA042

Kissimmee, Florida, 34746, United States

Location

USA039

Naples, Florida, 34102-5444, United States

Location

USA014

St. Petersburg, Florida, 33707, United States

Location

USA067

Tampa, Florida, 33606-3603, United States

Location

USA066

Augusta, Georgia, 30912-0004, United States

Location

USA029

Rincon, Georgia, 31326, United States

Location

USA037

Kansas City, Kansas, 66160, United States

Location

USA017

Baltimore, Maryland, 21224-3057, United States

Location

USA061

St Louis, Missouri, 63110-1035, United States

Location

USA069

Hillsborough, New Jersey, 08844-1528, United States

Location

USA065

Bayside, New York, 11361, United States

Location

USA011

New York, New York, 10017-6739, United States

Location

USA051

Durham, North Carolina, 27710-0001, United States

Location

USA025

Portland, Oregon, 97239, United States

Location

USA040

Philadelphia, Pennsylvania, 19104-4238, United States

Location

USA044

Anderson, South Carolina, 29621-5708, United States

Location

USA024

Charleston, South Carolina, 29414, United States

Location

USA022

Franklin, Tennessee, 37067-5603, United States

Location

USA021

McKinney, Texas, 75069-8085, United States

Location

USA052

Tyler, Texas, 75708-3154, United States

Location

ARG003

Córdoba, X5003DCE, Argentina

Location

AUS010

Chermside, Queensland, 4032, Australia

Location

AUS011

Woolloongabba, Queensland, 4102, Australia

Location

AUS008

Adelaide, South Australia, 5000, Australia

Location

AUT001

Linz, 4040, Austria

Location

DNK001

Roskilde, Zeeland, 4000, Denmark

Location

DNK004

Aalborg, DK-9000, Denmark

Location

DNK002

Aarhus, DK-8200, Denmark

Location

GER005

München, Bavaria, 80335, Germany

Location

GER010

Immenhausen, Hesse, 34376, Germany

Location

GER007

Hanover, Lower Saxony, 30625, Germany

Location

GER011

Cologne, North Rhine-Westphalia, 51109, Germany

Location

GER006

Dresden, 01307, Germany

Location

ISR001

Ashkelon, 78100, Israel

Location

ISR007

Haifa, 34362, Israel

Location

ISR003

Petah Tikva, 4910000, Israel

Location

ISR004

Ramat Gan, 52621, Israel

Location

ITA006

Modena, Emilia-Romagna, 41100, Italy

Location

ITA005

Rome, Lazio, 00168, Italy

Location

ITA008

Siena, Tuscany, 53100, Italy

Location

ITA002

Milan, 20162, Italy

Location

NZL003

Hastings, Hawkes's Bay, 4122, New Zealand

Location

NZL002

Hamilton, Waikato Region, 3204, New Zealand

Location

NZL001

Christchurch, 8461, New Zealand

Location

KOR005

Seongnam, 13620, South Korea

Location

KOR002

Seoul, 05505, South Korea

Location

KOR003

Seoul, 06973, South Korea

Location

ESP002

Barcelona, 08003, Spain

Location

ESP003

Barcelona, 8035, Spain

Location

ESP005

Girona, 17007, Spain

Location

ESP001

Madrid, 28034, Spain

Location

ESP004

Madrid, 28046, Spain

Location

TWN004

Chiayi City, Chiayi, 613, Taiwan

Location

TWN005

Kaohsiung City, 807, Taiwan

Location

TWN002

Taipei, 116, Taiwan

Location

Related Publications (1)

• Daley CL, Chalmers JD, Flume PA, Griffith DE, Hasegawa N, Morimoto K, Winthrop KL, Sheu CC, Avsar K, Andrisani D, Codecasa LR, Yuen DW, Hassan M, Nevoret ML, Mange K. Trial Conduct, Baseline Characteristics, and Symptom Burden of Patients in the ARISE Study. Pulm Ther. 2025 Jun;11(2):269-283. doi: 10.1007/s41030-025-00293-3. Epub 2025 Apr 8.

  PMID: 40198465 DERIVED

MeSH Terms

Conditions

Mycobacterium Infections, Nontuberculous; Mycobacterium avium-intracellulare Infection

Interventions

Azithromycin; Ethambutol

Condition Hierarchy (Ancestors)

Mycobacterium Infections; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections

Intervention Hierarchy (Ancestors)

Erythromycin; Macrolides; Polyketides; Lactones; Organic Chemicals; Ethylenediamines; Diamines; Polyamines; Amines

Results Point of Contact

• Title: Insmed Medical Information
• Organization: Insmed Incorporated

medicalinformation@insmed.com

1-844-446-7633

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 16, 2020
• First Posted: December 21, 2020
• Study Start: December 22, 2020
• Primary Completion: May 9, 2023
• Study Completion: May 9, 2023
• Last Updated: June 28, 2024
• Results First Posted: June 28, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

AU (1); DE (5); AR (1); ES (5); TW (3); KR (3); NZ (3); DK (3); IT (4); IL (4); US (27)