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

Mycobacterium Infections, Nontuberculous Clinical Trial

— ICoN-1  

Official title:

ICoN-1: A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study of the Efficacy and Safety of Clofazamine Inhalation Suspension When Added to Guideline-Based Therapy in Participants With Nontuberculous Mycobacterial Infection

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06418711
• Other study ID #: MKC-CI-002
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: June 2024
• Est. completion date: December 1, 2028

Study information

• Verified date: May 2024
• Source: Mannkind Corporation
• Contact: Kelley Snodgres
• Phone: 8186615000
• Email: ICoN1research[@]mannkindcorp.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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 Clofazamine Inhalation Suspension.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 234
• Est. completion date: December 1, 2028
• Est. primary completion date: August 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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).

Related Conditions & MeSH terms

• Communicable Diseases
• Infections
• Lung Diseases
• Mycobacterium Infections
• Mycobacterium Infections, Nontuberculous

Intervention

Drug:
• Clofazimine Inhalation Suspension
Eligible participants will be randomized in a 2:1 ratio to 1 of 2 possible treatment assignments, Clofazimine Inhalation Suspension or Placebo.
• Placebo
Eligible participants will be randomized in a 2:1 ratio to 1 of 2 possible treatment assignments, Clofazimine Inhalation Suspension or Placebo.

Locations

Country	Name	City	State
United States	Low Country Infectious Diseases	Charleston	South Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Mannkind Corporation

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	(Part A) Sputum NTM density in CFU/mL at the end of Month 6	(Part A) Sputum NTM density in CFU/mL at the end of Month 6	End of Month 6
Other	(Part A) Sputum NTM resistance patterns at the end of Month 6, measured using sputum microbiological lab assessments	(Part A) Sputum NTM resistance patterns at the end of Month 6, measured using sputum microbiological lab assessments	End of Month 6
Other	(Part A) Time to first negative NTM sputum culture in participants who achieve culture conversion by Month 6	(Part A) Time to first negative NTM sputum culture in participants who achieve culture conversion by Month 6	End of Month 6
Other	(Part A) Time to sputum culture conversion in participants who achieve culture conversion by Month 6	(Part A) Time to sputum culture conversion in participants who achieve culture conversion by Month 6	End of Month 6
Other	(Part A) Rate of sputum culture conversion (negative to positive) in the subgroup of study participants whose baseline sputum culture is negative for NTM	(Part A) Rate of sputum culture conversion (negative to positive) in the subgroup of study participants whose baseline sputum culture is negative for NTM	Baseline to end of study
Other	(Part A) Time-to-positivity (TTP) in broth cultures for NTM in sputum at the end of Months 1,2,3,4,5, and 6	(Part A) Time-to-positivity (TTP) in broth cultures for NTM in sputum at the end of Months 1,2,3,4,5, and 6	End of Months 1,2,3,4,5, and 6
Other	(Part A) Changes in inflammatory markers (specific tests to be determined) from baseline to the end of Month 6	(Part A) Changes in inflammatory markers (specific tests to be determined) from baseline to the end of Month 6	Baseline to the end of Month 6
Other	(Part A) Rate of pulmonary exacerbations, 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	(Part A) Rate of pulmonary exacerbations, 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	End of Months 1,2,3,4,5, and 6
Other	(Part A) Rate of respiratory-related (as defined by the investigator) hospitalization	(Part A) Rate of respiratory-related (as defined by the investigator) hospitalization	Baseline to end of Month 6
Other	(Part A) All-cause mortality	(Part A) All-cause mortality	Baseline to end of Month 6
Other	(Part A) Respiratory-related (as determined by the investigator) mortality	(Part A) Respiratory-related (as determined by the investigator) mortality	Baseline to end of Month 6
Other	(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	(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	Baseline to end of Month 6
Other	(Part A) Difference in days of absenteeism from work	(Part A) Difference in days of absenteeism from work	Baseline to end of Month 6
Other	(Part A) Difference in hospitalization days	(Part A) Difference in hospitalization days	Baseline to end of Month 6
Other	(Part A) Difference in number of emergency room visits	(Part A) Difference in number of emergency room visits	Baseline to end of Month 6
Other	(Part A) Difference in number of urgent care visits	(Part A) Difference in number of urgent care visits	Baseline to end of Month 6
Other	(Part A) Difference in number of unscheduled doctor visits	(Part A) Difference in number of unscheduled doctor visits	Baseline to end of Month 6
Other	(Part A) Change in BMI from baseline to the end of Month 6	(Part A) Change in BMI from baseline to the end of Month 6	Baseline to end of Month 6
Other	(Part A) Slope of the change from baseline to end of Month 6 in log10 CFU/mL	(Part A) Slope of the change from baseline to end of Month 6 in log10 CFU/mL	Baseline to end of Month 6
Other	(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	(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	Baseline to the end of Month 6
Other	(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	(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	Baseline to the end of Month 6
Other	(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	(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	Baseline to the end of Month 6
Other	(Part A) Concentration of clofazimine in serum	(Part A) Concentration of clofazimine in serum	Baseline to end of Month 6
Other	(Part A) Change in forced expiratory volume in 1 second (FEV1) from baseline to the end of Month 6	(Part A) Change in forced expiratory volume in 1 second (FEV1) from baseline to the end of Month 6	Baseline to the end of Month 6
Other	(Part A) Rate of study drug discontinuations	(Part A) Rate of study drug discontinuations	Baseline to end of Month 6
Other	(Part A) Rate of study drug dose reductions	(Part A) Rate of study drug dose reductions	Baseline to end of Month 6
Other	(Part A) Rate of treatment-emergent adverse events (TEAEs)	(Part A) Rate of treatment-emergent adverse events (TEAEs)	Baseline to end of Month 6
Other	(Part A) Rate of serious adverse events (SAEs)	(Part A) Rate of serious adverse events (SAEs)	Baseline to end of Month 6
Other	(Part A) Rate of laboratory abnormalities	(Part A) Rate of laboratory abnormalities	Baseline to end of Month 6
Other	(Part A) Rate of electrocardiogram (ECG) abnormalities	(Part A) Rate of electrocardiogram (ECG) abnormalities	Baseline to end of Month 6
Other	(Part B) Adverse Events (AEs) related to inhalation intolerability	(Part B) Adverse Events (AEs) related to inhalation intolerability	Study Month 7 through Study Month 22
Other	(Part B) AEs due to skin discoloration	(Part B) AEs due to skin discoloration	Study Month 7 through Study Month 22
Other	(Part B) AEs due to QTc changes	(Part B) AEs due to QTc changes	Study Month 7 through Study Month 22
Other	(Part B) Sputum culture conversion (i.e., 3 consecutive- monthly sputum cultures negative for NTM	(Part B) Sputum culture conversion (i.e., 3 consecutive- monthly sputum cultures negative for NTM	Study Month 7 through Study Month 22
Other	(Part B) Rate of sputum culture conversion (negative to positive) in the subgroup of study participants whose baseline sputum culture is negative	(Part B) Rate of sputum culture conversion (negative to positive) in the subgroup of study participants whose baseline sputum culture is negative	Study Month 7 through Study Month 22
Other	(Part B) Rate of persistency of negative sputum culture	(Part B) Rate of persistency of negative sputum culture	Study Month 7 through Study Month 22
Other	(Part B) Change in QoL-B RSS from baseline	(Part B) Change in QoL-B RSS from baseline	Study Month 7 through Study Month 22
Other	(Part B) Difference in days of absenteeism from work	(Part B) Difference in days of absenteeism from work	Study Month 7 through Study Month 22
Other	(Part B) Difference in hospitalization days	(Part B) Difference in hospitalization days	Study Month 7 through Study Month 22
Other	(Part B) Difference in number of emergency room visits	(Part B) Difference in number of emergency room visits	Study Month 7 through Study Month 22
Other	(Part B) Difference in number of urgent care visits	(Part B) Difference in number of urgent care visits	Study Month 7 through Study Month 22
Other	(Part B) Difference in number of unscheduled doctor visits	(Part B) Difference in number of unscheduled doctor visits	Study Month 7 through Study Month 22
Other	(Part B) Sustainability of response to Clofazimine Inhalation Suspension, evaluated quarterly while on treatment following initial conversion, for participants who convert	(Part B) Sustainability of response to Clofazimine Inhalation Suspension, evaluated quarterly while on treatment following initial conversion, for participants who convert. Culture conversion with sustainability is defined as achieving culture conversion and then having no more than 2 consecutive broth or Agar positive sputum cultures and no Agar positive culture observed once initial conversion is achieved.	Study Month 7 through Study Month 22
Other	(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	(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. Culture conversion with durability is defined as achieving culture conversion and remaining a converter at the end of active treatment and then having no broth or Agar positive sputum culture following active treatment	Study Month 7 through Study Month 22
Primary	(Part A) Sputum culture conversion (i.e., 3 consecutive monthly sputum cultures negative for NTM) by the end of Month 6	(Part A) Sputum culture conversion (i.e., 3 consecutive monthly sputum cultures negative for NTM) by the end of Month 6 (Part A)	Baseline to the end of Month 6
Primary	(Part A) Change in QoL-B RSS from baseline to end of Month 6 (Part A)	(Part A) Change in QoL-B RSS from baseline to end of Month 6 (Part A)	Baseline to end of Month 6
Secondary	(Part A) Time to a composite endpoint of pulmonary exacerbation, 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)	(Part A) Time to a composite endpoint of pulmonary exacerbation, 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 IV) antibiotic use for NTM or other pneumonia treatment (Part A)	Baseline to the end of Month 6
Secondary	(Part A) Change in 6-minute walk distance (6MWD) from baseline to the end of Month 6	(Part A) Change in 6-minute walk distance (6MWD) from baseline to the end of Month 6	Baseline to the end of Month 6
Secondary	(Part A) Change in participant identified Most Bothersome Symptom (MBS) from baseline to the end of Month 6	(Part A) Change in participant identified Most Bothersome Symptom (MBS) from baseline to the end of Month 6	Baseline to the end of Month 6
Secondary	(Part A) Change in response to the Patient Global Impression of Severity (PGI-S) questionnaire from baseline to the end of Month 6	(Part A) Change in response to the Patient Global Impression of Severity (PGI-S) questionnaire from baseline to the end of Month 6	Baseline to the end of Month 6
Secondary	(Part A) Response to the Patient Global Impression of Change (PGI-C) questionnaire at the end of Month 6	(Part A) Response to the Patient Global Impression of Change (PGI-C) questionnaire at the end of Month 6	Baseline to the end of Month 6