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ICoN-1: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of the Efficacy and Safety of Treatment With MNKD-101 (Clofazimine Inhalation Suspension) When Added to Guideline-Based Therapy in Participants with Pulmonary Nontuberculous Mycobacterial Infection (Part A) Followed by an Open-Label Extension (Part B)

ICoN-1: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of the Efficacy and Safety of Treatment With MNKD-101 (Clofazimine Inhalation Suspension) When Added to Guideline-Based Therapy in Participants with Pulmonary Nontuberculous Mycobacterial Infection (Part A) Followed by an Open-Label Extension (Part B)

Suzaki Keiko

EPS Corporation

2-23 Shimomiyabicho, Shinjuku-ku, Tokyo

jrct-inquiry@eps.co.jp

EPS Corporation jRCT inquiry reception center

EPS Corporation

2-23 Shimomiyabicho, Shinjuku-ku, Tokyo, 162-0822

+81-3-5684-7797

jrct-inquiry@eps.co.jp

Suspended

Nov. 20, 2024

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1. Evidence of signed and dated informed consent document(s) indicating that 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 at screening.
3. Evidence of underlying nodular bronchiectasis and/or fibrocavitary disease on a chest radiograph or chest computed tomography, as determined by the investigator, within the12 months prior to screening.
4. MAC-positive culture results from at least two separate (at least 1 week apart) sputum samples, one taken within 12 months, and another taken within 3 months prior to the date of informed consent. The most recent sputum culture with available results should be expectorated (e.g., not collected via bronchoscopy) and positive for MAC. The time windows are based on the dates the samples are taken, not the dates of analysis or reporting. Note: A sputum culture will be obtained at baseline, but the participant may be randomized prior to availability of the results. (Coinfection with another NTM species including M. abscessus is allowed).
5. Be able to produce at least 3 mL of sputum or be willing to undergo a sputum 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 to participate 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 postmenopausal 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 protocolrecommended method of contraception from the start of the study therapy until >=12 months after the final dose of the 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.
11. Participants who have co-infection with another NTM species in addition to MAC, the MAC should be the predominant NTM species assessed by the investigator based on the clinical judgment of the investigator.

1. Clinical diagnosis of 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., minimum inhibitory concentration (MIC) >=8 microgram/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 or device 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 for 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 4 months) initiation of or increase 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, per the investigator's clinical judgment.
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 of 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 the upper limit of normal (ULN) or total bilirubin > 1.5 times ULN during screening.
22. Absolute neutrophil count <500/microliter during screening.
23. Use of prednisone >=10 mg/day within 3 months prior to screening, or other significant immunosuppression as deemed by the investigator.
24. Estimated glomerular filtration rate <30 mL/minute/1.73 m2 (according to the chronic kidney disease-epidemiology (CKD-EPI) 2021 creatinine equation) during screening.
25. Advanced liver disease (Child-Pugh Class A, B, or C)
26. A lung cavity on chest imaging of >5 cm in widest diameter based on latest imaging, as reported by the investigator.

Both

Pulmonary nontuberculous mycobacterial infection caused by Mycobacterium avium complex (MAC)

During the randomized, double-blind, placebo-controlled study period, MNKD-101 80 mg or placebo will be administered by inhalation once daily. Dose for 28 days followed by a 56-day rest period (Cycle 1).Thereafter, one cycle is repeated in the same way (Cycle 2). If eligible after completion of blinded treatment, the patient will be transferred to the open-label extension study. During the open-label extension study, MNKD-101 80 mg once daily inhalation administaration. Dose for 28 days, followed by a 56-day rest period and repeat for a maximum of 18 months (6 cycles). During both periods, if the participant is intolerant, a dose reduction to MNKD-101 50 mg is allowed. Both period and dose groups, guideline-based therapy (GBT) will be combined with MNKD-101.

(Double-Blind Period) Primary Efficacy Endpoint:
Sputum culture conversion (i.e., 3 consecutive monthly sputum cultures negative for MAC) by the end of Month 6
(Open-Label Extension Period) Primary Endpoint:
Long-term safety profile of Clofazimine Inhalation Suspension, including inhalation tolerability, skin discoloration, and QTc changes

(Double-Blind Period) Secondary Efficacy Endpoints:
1. Change in QoL-B RSS from baseline to the end of Month 6 (key secondary endpoint)
2. Time to a composite endpoint of pulmonary exacerbation (key secondary endpoint), defined as the occurrence of any of the following clinical events: all-cause mortality, respiratory-related (as determined by the investigator) hospitalization, or the requirement for parenteral (inhaled or intravenous [IV]) antibiotic use for NTM or other pneumonia treatment
3. Change in 6MWD from baseline to the end of Month 6 (key secondary endpoint)
4. Change in participant-identified MBS from baseline to the end of Month 6 and at intermediate visits
5. Change in response to the PGI-S questionnaire from baseline to the end of Month 6 (anchor for the change in QoL-B RSS from baseline to the end of Month 6) and at intermediate visits
6. Response to the PGI-C questionnaire at the end of Month 6 (anchor for the change in QoL-B RSS from baseline to the end of Month 6) and at intermediate visits

(Open-Label Extension Period)Secondary Endpoints:
1. Sputum culture conversion (i.e., 3 consecutive monthly sputum cultures negative for MAC)
2. Sputum culture conversion (i.e., 3 consecutive monthly sputum cultures negative for all NTM)
3. Rate of sputum culture conversion (MAC-negative to MAC-positive) in the subgroup of study participants whose Part A baseline sputum culture is negative for MAC
4. Rate of sputum culture conversion (MAC-negative to MAC-positive) in the subgroup of study participants whose Part B baseline sputum culture is negative for MAC
5. Rate of persistency of negative sputum culture
6. Change in QoL-B RSS from baseline
7. Difference in burden of disease as assessed by parameters including absenteeism from work, days in hospital, emergency room visits, urgent care visits, and unscheduled doctor visits
8. Sustainability of response to Clofazimine Inhalation Suspension, evaluated quarterly for 12 months while on treatment following initial sputum culture conversion, for participants who convert
9. Durability of response to Clofazimine Inhalation Suspension, evaluated quarterly for 12 months following the end of treatment, for participants who remain converters at the end of treatment

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