Clinical trial NCT06418711: ICoN-1 Phase 3 Study of the Efficacy and Safety of Treatment With MNKD-101, Clofazimine Inhalation Suspension
Official title: ICoN-1: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of the Efficacy and Safety of Clofazimine Inhalation Suspension When Added to Guideline-Based Therapy in Participants With Nontuberculous Mycobacterial Infection
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: MAC Lung Disease
Treatment Refractory MAC Lung Disease
Mycobacterium Infections, Nontuberculous
Keywords: Bronchiectasis
NTM (Nontuberculous mycobacteria)
MAC (Mycobacterium avium complex)
MABSC (Mycobacterium abscessus complex)
Pulmonary Nontuberculous Mycobacteria
Respiratory Infection
antimycobacterial activity
antimycobacterial therapy
MAC infections
MAC Lung disease
MAC pulmonary infection
Mycobacteria
mycobacterium
Mycobacterium Avium Complex Infections
Mycobacterium avium complex lung disease
mycobacterium Infections
Nontuberculous
Non-tuberculous mycobacterial (NTM) infections
Nontuberculous mycobacterial lung disease
Non-tuberculous mycobacterial pulmonary disease
NTM infection
NTM lung disease
NTM Pulmonary Disease
NTM lung infection
Pulmonary MAC disease
Pulmonary Mycobacterium Avium Complex disease
Treatment refractory MAC lung disease
Treatment refractory mycobacterial lung disease
Treatment refractory NTM lung infection
Treatment refractory NTM pulmonary disease
Respiratory Tract diseases
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Bacterial Infections and Mycoses
Infections
Mycobacterium Infections, Nontuberculous
Mycobacterium avium-intracellulare Infection
Lung diseases
Anti-Bacterial Agents
Anti-infective Agents
Antitubercular Agents
Azithromycin
Amikacin
Ethambutol
Clofazimine
Lamprene
Lead sponsor: Mannkind Corporation
Sponsor class: INDUSTRY
First posted: 2024-05-17
Enrollment: 234
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: At least 234 eligible participants will be randomized in a 2:1 ratio of 1 of 2 possible treatment assignments in order to ensure that a minimum of 180 participants are evaluable for efficacy: Clofazimine Inhalation Suspension (N=120) and placebo (n=60). Randomization will be stratified by type of nontuberculous mycobacteria (NTM) infection (Mycobacterium avium complex \[MAC\] infection only vs MAC co-infection with Mycobacterium abscessus complex \[MABSC\] or other NTM species) based on historical samples used to establish eligibility during screening. Enrollment of participants with MAC coinfection with MABSC or other NTM species will be capped at 20% of all participants to limit heterogeneity in the participant population.
Primary purpose: TREATMENT

Brief summary: This clinical trial is designed to compare the efficacy and safety of Clofazimine Inhalation Suspension versus placebo when added to guideline-based therapy (GBT)

Detailed description: Randomized, double-blind, placebo-controlled study (Part A) designed to compare the efficacy and safety of Clofazimine Inhalation Suspension versus placebo when added to guideline-based therapy (GBT). The primary objective of this study will be to compare the efficacy of Clofazimine Inhalation Suspension versus placebo as assessed by the co-primary endpoints, sputum culture conversion and change in Quality of Life-Bronchiectasis Respiratory Symptoms Score (QoL-B RSS).

An open label extension study (Part B) will be offered to qualified participants for treatment with Clofazimine Inhalation Suspension.

Eligibility criteria: Inclusion Criteria:

1. Evidence of signed and dated informed consent document(s) indicating the participant has been informed of all pertinent aspects of the trial.
2. Age ≥18 years or legal age for the participating country (e.g., the legal age in South Korea is 19 years) and ≤85 years.
3. Evidence of underlying nodular bronchiectasis and/or fibrocavitary disease on a chest radiograph or chest computed tomography, as determined by the investigator, within the last 12 months.
4. MAC-positive culture results from at least two separates (at least 1 week apart) expectorated sputum samples, one taken within 12 months, and another taken within 3 months prior to the date of informed consent. Note: A sputum culture will be obtained at baseline, but the participant may be randomized prior to availability of the results.
5. Be able to produce at least 3 mL of sputum or be willing to undergo an induction that produces at least 3 mL of sputum for mycobacteriology.
6. FEV1 ≥40% of predicted during screening, as calculated by the local spirometry laboratory standards.
7. Currently receiving a multi-drug regimen of GBT for pulmonary NTM infection in line with the 2020 ATS/ERS/ESCMID/IDSA guideline for the treatment of NTM pulmonary disease for at least 6 months prior to consenting in this study, with no changes in this regimen within 2 months of screening.
8. For female participants of childbearing potential, a negative serum pregnancy test and agreement to use a protocol-recommended method of contraception during heterosexual intercourse from the start of the screening period until ≥12 months after the final dose of study therapy. Note: A female participant is considered to be of childbearing potential, i.e., fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
9. For male participants who can father a child and are having intercourse with females of childbearing potential, agreement to use a protocol-recommended method of contraception from the start of the study therapy until ≥12 months after the final dose of study therapy and to refrain from sperm donation from the start of study therapy until ≥12 months after administration of the final dose of study therapy. Note: A male participant is considered fertile after puberty unless permanently sterile by bilateral orchidectomy.
10. Willingness and ability to comply with scheduled visits, drug inhalation plan, study procedures, laboratory tests, and study restrictions.

Exclusion Criteria:

1. Cystic fibrosis.
2. Active tuberculosis. Note: Participants with a history of treated latent or active tuberculosis may be eligible as long as their sputum cultures in the last year are negative for tuberculosis and they are deemed by the investigator as not having current active tuberculosis.
3. Disseminated MAC or MABSC infection or participants with isolated MABSC infection.
4. Recent (i.e., within the last 3 months from date of screening) ICU admission with or without mechanical ventilation.
5. Inability to inhale with a nebulizer, in the opinion of the investigator.
6. Participants with known hypersensitivity to any of the ingredients or excipients of clofazimine.
7. Prior therapy with clofazimine in the previous 4 months from date of screening.
8. Participants with known resistance to clofazimine as treatment for MAC (i.e., MIC \>8 ug/mL for MAC).
9. Prior therapy with amikacin by any route of administration (e.g., inhaled or IV) in the previous 2 months from date of screening.
10. Ongoing participation in any other interventional drug or device clinical trial, or exposure to another investigational drug within 28 days prior to start of study treatment. Note: For investigational therapies that have a prolonged half-life, a case-by-case assessment will be made regarding the required washout period prior to being eligible for this study.
11. Current (or planned during the study) pregnancy or breastfeeding.
12. QT prolongation during screening (450 ms or longer), and/or uncontrolled sinus rhythm (\>110/minute).
13. Increased risk of proarrhythmia (e.g., recent \[within 6 months\] myocardial infarction, stroke, heart failure decompensation or left ventricular ejection of \<45%, ventricular arrhythmias, torsade de pointes, unstable angina, or high-degree atrioventricular block).
14. A family history of sudden cardiac death, unexplained death, long-QT syndrome, or death from a primary dysrhythmia potentially associated with QT prolongation.
15. Recent (within 6 months) initiation of or change in the dosing regimen of any concomitant medication that is known to prolong the QT interval. Note: Participants who are on a stable regimen, in the opinion of the investigator, of the concomitant medication during screening are eligible.
16. Chronic and clinically meaningful, in the opinion of the investigator, abnormalities in potassium, magnesium, or calcium levels.
17. Active pulmonary malignancy (primary or metastatic) or any malignancy requiring chemotherapy or radiation therapy within 3 years before screening or anticipated during the study period.
18. Current alcohol, medication, or illicit drug abuse.
19. Prior or ongoing social or medical condition (e.g., concomitant illness, psychiatric condition, behavioral disorder), medical history, physical findings, ECG findings or laboratory abnormality that, in the opinion of the investigator, could adversely affect the safety of the participant, makes it unlikely that the course treatment or follow-up would be completed, or could impair the assessment of study results.
20. Any prior use of bedaquiline within 1 year of screening.
21. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>1.5 times upper limit of normal (ULN) or total bilirubin \>1.5 times ULN during screening.
22. Absolute neutrophil count \<500/µL during screening.
23. Use of prednisone ≥10mg/day within 3 months prior to screening, or other significant immunosuppression as deemed by the investigator.
24. Estimated glomerular filtration rate \<30mL/minute/1.73 m2 (according to the CKD-EPI 2021 creatine equation) during screening.
25. Advanced liver disease (Child-Pugh Class A, B, or C).

Primary outcomes:
measure: (Part A) Sputum culture conversion (i.e., 3 consecutive monthly sputum cultures negative for MAC) by the end of Month 6
timeFrame: Baseline to the end of Month 6
measure: (Part A) Change in QoL-B RSS from baseline to end of Month 6 (Part A)
timeFrame: Baseline to end of Month 6
Secondary outcomes:
measure: (Part A) Time to a composite endpoint of pulmonary worsening, as defined by: all-cause mortality, respiratory-related hospitalization, or the requirement for parenteral (inhaled or IV) antibiotic use for NTM or other pneumonia treatment (Part A)
timeFrame: Baseline to the end of Month 6
measure: (Part A) Change in 6-minute walk distance (6MWD) from baseline to the end of Month 6
timeFrame: Baseline to the end of Month 6
measure: (Part A) Change in participant identified Most Bothersome Symptom (MBS) from baseline to the end of Month 6
timeFrame: Baseline to the end of Month 6
measure: (Part A) Change in response to the Patient Global Impression of Severity (PGI-S) questionnaire from baseline to the end of Month 6
timeFrame: Baseline to the end of Month 6
measure: (Part A) Response to the Patient Global Impression of Change (PGI-C) questionnaire at the end of Month 6
timeFrame: Baseline to the end of Month 6
Other outcomes:
measure: (Part A) Sputum MAC density in CFU/mL at the end of Month 6
timeFrame: End of Month 6
measure: (Part A) Sputum MAC resistance patterns at the end of Month 6, measured using sputum microbiological lab assessments
timeFrame: End of Month 6
measure: (Part A) Time to first negative MAC sputum culture in participants who achieve culture conversion by Month 6
timeFrame: End of Month 6
measure: (Part A) Time to sputum culture conversion in participants who achieve culture conversion by Month 6
timeFrame: End of Month 6
measure: (Part A) Rate of sputum culture conversion (MAC-negative to MAC-positive) in the subgroup of study participants whose baseline sputum culture is negative for NTM
timeFrame: Baseline to end of study
measure: (Part A) Time-to-positivity (TTP) in broth cultures for MAC in sputum at the end of Months 1,2,3,4,5, and 6
timeFrame: End of Months 1,2,3,4,5, and 6
measure: (Part A) Changes in inflammatory markers (specific tests to be determined) from baseline to the end of Months 1,3,4, and 6
timeFrame: End of Months Months 1,3,4, and 6
measure: (Part A) Rate of pulmonary worsening, as diagnosed and defined by the investigator based upon a participant's need for a limited course of antibiotic medication to treat an acute worsening of symptoms, in Months 1,2,3,4,5, and 6
timeFrame: End of Months 1,2,3,4,5, and 6
measure: (Part A) Rate of respiratory-related (as defined by the investigator) hospitalization
timeFrame: Baseline to end of Month 6
measure: (Part A) All-cause mortality
timeFrame: Baseline to end of Month 6
measure: (Part A) Respiratory-related (as determined by the investigator) mortality
timeFrame: Baseline to end of Month 6
measure: (Part A) Use of rescue medication (i.e., initiation of anti-mycobacterial medication that is recommended by the investigator due to a perception of lack of efficacy of study drug) for pulmonary NTM infection
timeFrame: Baseline to end of Month 6
measure: (Part A) Difference in days of absenteeism from work
timeFrame: Baseline to end of Month 6
measure: (Part A) Difference in hospitalization days
timeFrame: Baseline to end of Month 6
measure: (Part A) Difference in number of emergency room visits
timeFrame: Baseline to end of Month 6
measure: (Part A) Difference in number of urgent care visits
timeFrame: Baseline to end of Month 6
measure: (Part A) Difference in number of unscheduled doctor visits
timeFrame: Baseline to end of Month 6
measure: (Part A) Change in BMI from baseline to the end of Month 6
timeFrame: Baseline to end of Month 6
measure: (Part A) Slope of the change from baseline to end of Month 6 in log10 CFU/mL of MAC
timeFrame: Baseline to end of Month 6
measure: (Part A) Changes in other QoL-B questionnaire domain (Physical, Role, Emotional and Social Functioning, Vitality, Health Perceptions and Treatment Burden) scores from baseline to the end of Month 6
timeFrame: Baseline to the end of Month 6
measure: (Part A) Changes in shortness of breath when sitting or at rest and when exercising from baseline to the end of Month 6, measured using stand-alone shortness of breath questionnaire
timeFrame: Baseline to the end of Month 6
measure: (Part A) Change in most severe symptom at baseline from baseline to the end of Month 6, measured using stand-alone shortness of breath questionnaire
timeFrame: Baseline to the end of Month 6
measure: (Part A) Concentration of clofazimine in plasma
timeFrame: Baseline to end of Month 6
measure: (Part A) Change in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) from baseline to the end of Month 6
timeFrame: Baseline to the end of Month 6
measure: (Part A) Rate of study drug discontinuations
timeFrame: Baseline to end of Month 6
measure: (Part A) Rate of study drug dose reductions
timeFrame: Baseline to end of Month 6
measure: (Part A) Rate of treatment-emergent adverse events (TEAEs)
timeFrame: Baseline to end of Month 6
measure: (Part A) Rate of treatment-related adverse events (TRAEs)
timeFrame: Baseline to end of Month 6
measure: (Part A) Rate of serious adverse events (SAEs)
timeFrame: Baseline to end of Month 6
measure: (Part A) Rate of laboratory abnormalities
timeFrame: Baseline to end of Month 6
measure: (Part A) Rate of electrocardiogram (ECG) abnormalities
timeFrame: Baseline to end of Month 6
measure: (Part B) Adverse Events (AEs) related to inhalation intolerability
timeFrame: Study Month 7 through Study Month 22
measure: (Part B) AEs due to skin discoloration
timeFrame: Study Month 7 through Study Month 22
measure: (Part B) AEs due to QTc changes
timeFrame: Study Month 7 through Study Month 22
measure: (Part B) Sputum culture conversion (i.e., 3 consecutive- monthly sputum cultures negative for NTM
timeFrame: Study Month 7 through Study Month 22
measure: (Part B) Rate of sputum culture conversion (MAC-negative to MAC-positive) in the subgroup of study participants whose baseline sputum culture is negative
timeFrame: Study Month 7 through Study Month 22
measure: (Part B) Rate of persistency of negative sputum culture
timeFrame: Study Month 7 through Study Month 22
measure: (Part B) Change in QoL-B RSS from baseline
timeFrame: Study Month 7 through Study Month 22
measure: (Part B) Difference in days of absenteeism from work
timeFrame: Study Month 7 through Study Month 22
measure: (Part B) Difference in hospitalization days
timeFrame: Study Month 7 through Study Month 22
measure: (Part B) Difference in number of emergency room visits
timeFrame: Study Month 7 through Study Month 22
measure: (Part B) Difference in number of urgent care visits
timeFrame: Study Month 7 through Study Month 22
measure: (Part B) Difference in number of unscheduled doctor visits
timeFrame: Study Month 7 through Study Month 22
measure: (Part B) Sustainability of response to Clofazimine Inhalation Suspension, evaluated quarterly while on treatment following initial conversion, for participants who convert
timeFrame: Study Month 7 through Study Month 22
measure: (Part B) Durability of response to Clofazimine Inhalation Suspension, evaluated quarterly following active treatment, for participants who remain converters at the end of active treatment
timeFrame: Study Month 7 through Study Month 22
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham School of Medicine
state: Alabama
city: Fresno
country: United States
facility: University of California San Francisco Fresno
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Newport Beach
country: United States
facility: Hoag Hospital
state: California
city: Sacramento
country: United States
facility: University of California Davis Medical Center
state: California
city: San Francisco
country: United States
facility: University of California San Francisco
state: California
city: Santa Barbara
country: United States
facility: Santa Barbara Cottage Hospital
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Denver
country: United States
facility: National Jewish Health
state: Colorado
city: Farmington
country: United States
facility: UCONN Health
state: Connecticut
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Washington
country: United States
facility: Georgetown University Hospital
state: District of Columbia
city: Washington
country: United States
facility: The George Washington University Medical Faculty Associates
state: District of Columbia
city: Bay Pines
country: United States
facility: VA Bay Pines
state: Florida
city: Clearwater
country: United States
facility: St. Francis Sleep, Allergy & Lung Institute
state: Florida
city: Gainesville
country: United States
facility: Malcolm Randall Veterans Affairs Medical Center
state: Florida
city: Jacksonville
country: United States
facility: University of Florida College of Medicine
state: Florida
city: Saint Petersburg
country: United States
facility: Theia Clinical Research
state: Florida
city: Sebastian
country: United States
facility: Infectious Diseases Consultants of the Treasure Coast
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: West Palm Beach
country: United States
facility: Midway Specialty Care Center
state: Florida
city: Weston
country: United States
facility: Cleveland Clinic
state: Florida
city: Winter Park
country: United States
facility: Flourish Research
state: Florida
city: Atlanta
country: United States
facility: Emory University School Of Medicine
state: Georgia
city: Valdosta
country: United States
facility: Medster Research
state: Georgia
city: Honolulu
country: United States
facility: The Queen's Medical Center
state: Hawaii
city: Iowa City
country: United States
facility: University of Iowa Hospital and Clinics
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Wichita
country: United States
facility: Infectious Disease Consultants Clinical Research
state: Kansas
city: New Orleans
country: United States
facility: Ochsner Clinic Foundation
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins University School of Medicine
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Detroit
country: United States
facility: Henry Ford Hospital
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Columbia
country: United States
facility: University of Missouri
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: Newark
country: United States
facility: Rutgers New Jersey Medical School
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New Hyde Park
country: United States
facility: Northwell Health
state: New York
city: New York
country: United States
facility: NYU Langone Health
state: New York
city: New York
country: United States
facility: Mount Sinai-National Jewish Respiratory Institute
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Queens
country: United States
facility: NYC Health and Hospitals-Elmhurst
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina at Chapel Hill
state: North Carolina
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: Temple Lung Center
state: Pennsylvania
city: West Reading
country: United States
facility: Reading Hospital
state: Pennsylvania
city: Anderson
country: United States
facility: AnMed Health
state: South Carolina
city: Charleston
country: United States
facility: Low Country Infectious Diseases
state: South Carolina
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: North Texas Infectious Diseases Consultants
state: Texas
city: Tyler
country: United States
facility: The University of Texas Health Science Center
state: Texas
city: Charlottesville
country: United States
facility: UVA Health Infectious Diseases Clinic
state: Virginia
city: Sydney
country: Australia
facility: Macquarie University Clinical Trials Unit
state: New South Wales
city: Birtinya
country: Australia
facility: Sunshine Coast University Hospital
state: Queensland
city: Brisbane
country: Australia
facility: The Prince Charles Hospital
state: Queensland
city: Greenslopes
country: Australia
facility: Gallipoli Medical Research Foundation
state: Queensland
city: Fukuoka
country: Japan
facility: National Hospital Organization Omuta National Hospital
city: Ibaraki
country: Japan
facility: Ibarakihigashi National Hospital
city: Kamogawa-shi
country: Japan
facility: Kameda Clinic
city: Kyoto
country: Japan
facility: Minami Kyoto Hospital
city: Matsusaka
country: Japan
facility: Matsusaka Municipal Hospital
city: Niigata
country: Japan
facility: Nishiniigata Chuo Hospital
city: Osaka
country: Japan
facility: National Hospital Organization - Osaka Toneyama Medical Center
city: Sakai-city
country: Japan
facility: National Hospital Organization Kinki-Chuo Chest Medical Center
city: Shinjuku-ku
country: Japan
facility: Keio University Hospital
city: Shizuoka
country: Japan
facility: National Hospital Organization Tenryu Hospital
city: Gwangju
country: Korea, Republic of
facility: Chonnam National University Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea Seoul St.Mary's Hospital
Study officials:
affiliation: Mannkind Corporation
name: Wassim Fares, MD
role: STUDY_DIRECTOR
References: