ICoN-1 Phase 3 Study of the Efficacy and Safety of Treatment With MNKD-101, Clofazimine Inhalation Suspension

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

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).