Clofazimine Inhalation for Nontuberculous Mycobacterial Infections

(ICoN-1 Trial)

No longer recruiting at 111 trial locations

Overseen By Maria Oberdick

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Mannkind Corporation

Must be taking: Guideline-based therapy

Must not be taking: Amikacin, Bedaquiline, Prednisone

Disqualifiers: Cystic fibrosis, Active tuberculosis, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial evaluates the effectiveness and safety of a new inhaled treatment, Clofazimine Inhalation Suspension, for individuals with nontuberculous mycobacterial (NTM) lung infections. Participants will receive either the Clofazimine treatment or a placebo, both alongside their current guideline-based treatment plan. Suitable candidates have NTM infections identified in their sputum cultures and have maintained a stable multi-drug treatment for at least six months without recent changes. The trial involves inhaling the treatment using a nebulizer for specific cycles to test its impact on lung health and infection control. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the opportunity to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial requires participants to have been on a stable multi-drug regimen for their lung infection for at least 6 months before joining, with no changes in the last 2 months. This suggests you should continue your current medications as long as they meet these criteria.

Is there any evidence suggesting that Clofazimine Inhalation Suspension is likely to be safe for humans?

Research has shown that Clofazimine Inhalation Suspension is likely safe to use. Studies have examined its safety and pharmacokinetics, revealing that this treatment is generally well-tolerated, with most patients experiencing no serious side effects.

Reports indicate that most people handle the treatment well, with no major adverse reactions commonly reported in early studies. This suggests the treatment is safe for use.

Overall, the evidence supports the safety of Clofazimine Inhalation Suspension for treating lung infections caused by nontuberculous mycobacteria, a type of bacteria. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Clofazimine Inhalation Suspension is unique because it offers a novel inhalation delivery method for treating nontuberculous mycobacterial (NTM) infections, which typically rely on oral or intravenous antibiotics like azithromycin, ethambutol, and rifampin. This inhaled treatment directly targets the lungs, where NTM infections thrive, potentially increasing effectiveness and reducing systemic side effects compared to traditional therapies. Researchers are excited about this treatment because it leverages the antimicrobial properties of clofazimine in a concentrated format that may enhance drug penetration and action in the lungs, offering a promising alternative to existing regimens.

What evidence suggests that Clofazimine Inhalation Suspension might be an effective treatment for nontuberculous mycobacterial infections?

Research has shown that Clofazimine Inhalation Suspension, which participants in this trial may receive, might effectively treat lung infections caused by nontuberculous mycobacteria (NTM). Studies have found that delivering clofazimine directly to the lungs can better target the infection. This method may improve treatment outcomes by increasing the antibiotic concentration where it is needed most. Early research also suggests that this treatment is generally safe and well-tolerated by patients. Overall, these findings support the potential effectiveness of Clofazimine Inhalation Suspension for treating NTM infections. ^{2 3 4 6 7}

Who Is on the Research Team?

Wassim Fares, MD

Principal Investigator

Mannkind Corporation

Are You a Good Fit for This Trial?

Adults aged 18-85 with lung disease caused by Mycobacterium Avium Complex (MAC), who are already on a multi-drug regimen for at least 6 months, can produce sputum samples, and have no recent use of certain drugs or conditions like active cancer. Women must not be pregnant and agree to contraception; men must also agree to contraception if they can father children.

Inclusion Criteria

FEV1 ≥40% of predicted during screening

I can produce the required amount of sputum for the test.

I have been on a specific treatment for NTM lung infection for at least 6 months without changes.

Exclusion Criteria

Inability to inhale with a nebulizer, in the opinion of the investigator

Known hypersensitivity to any of the ingredients or excipients of clofazimine

I haven't had cancer treatments in the last 3 years and don't expect any during the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment (Part A)

Participants receive Clofazimine Inhalation Suspension or placebo daily for 28 days in Cycle 1, followed by 56 days off treatment, and then resume daily for 28 days in Cycle 2

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Open-label extension (Part B)

Qualified participants receive Clofazimine Inhalation Suspension from Study Month 7 through Study Month 22

16 months

What Are the Treatments Tested in This Trial?

Interventions

• Clofazimine Inhalation Suspension

Trial Overview The trial is testing the effectiveness and safety of Clofazimine Inhalation Suspension compared to a placebo in patients with MAC lung disease. Participants will continue their current drug regimens alongside the trial medication or placebo.

How Is the Trial Designed?

Group I: Clofazimine Inhalation Suspension Experimental Treatment 1 Intervention

MNKD-101 (Clofazimine Inhalation Suspension) is a micronized suspension with a concentration of 20 mg/mL. Study drug will be inhaled using the PARI breath-enhanced jet nebulizer system daily for 28 days in Cycle 1. Cycle 2 will commence after 56 days off treatment and resume daily for 28 days. Dose: 80 mg

Group II: Placebo Placebo Group 1 Intervention

The placebo is comprised of isotonic saline (0.9% weight/volume sodium chloride). Study drug will be inhaled using the PARI breath-enhanced jet nebulizer system daily for 28 days in Cycle 1. Cycle 2 will commence after 56 days off treatment and resume daily for 28 days.

Clofazimine Inhalation Suspension is already approved in United States, Japan for the following indications:

Approved in United States as MNKD-101 for:

• Nontuberculous mycobacterial (NTM) lung disease

Approved in Japan as MNKD-101 for:

• Nontuberculous mycobacterial (NTM) lung disease

Who Is Running the Clinical Trial?

Mannkind Corporation

Lead Sponsor

Trials

61

Recruited

8,400+

Michael E. Castagna

Mannkind Corporation

Chief Executive Officer since 2017

PharmD from Massachusetts College of Pharmacy & Sciences, MBA from The Wharton School of Business at the University of Pennsylvania

Burkhard Blank

Mannkind Corporation

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

In a study of 44 patients with nontuberculous mycobacterial (NTM) infections treated with clofazimine, 58% achieved treatment success, indicating that clofazimine can be an effective addition to multi-class antibiotic regimens for these difficult-to-treat infections.

Clofazimine was well-tolerated among patients, and those infected with the Mycobacterium abscessus group had a higher likelihood of treatment success, while macrolide resistance was associated with poorer outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clofazimine for treatment of multidrug-resistant non-tuberculous mycobacteria. Pfaeffle, HOI., Alameer, RM., Marshall, MH., et al.[2021]

Clofazimine has been identified as an ideal positive control for preclinical studies on Mycobacteroides abscessus (Mab) pulmonary disease, as it is well-tolerated, requires only once-daily dosing, and effectively reduces Mab burden in mouse models.

In a six-week study with C3HeB/FeJ and BALB/c mice, clofazimine at a dosage of 25 mg/kg once daily significantly decreased Mab levels in the lungs, supporting its use in future efficacy assessments of new treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clofazimine as a comparator for preclinical efficacy evaluations of experimental therapeutics against pulmonary M. abscessus infection in mice. Sriram, D., Wahi, R., Maggioncalda, EC., et al.[2023]

Clofazimine (CFZ) combined with clarithromycin (CLR) and ethambutol (EMB) significantly reduced lung bacterial counts in a mouse model of Mycobacterium avium, showing improved efficacy compared to untreated controls.

While CFZ added to CLR enhanced treatment effectiveness, it was less effective than the standard CLR-RIF-EMB combination, indicating that while CFZ shows promise, further studies are needed to optimize its use in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synergistic Activity of Clofazimine and Clarithromycin in an Aerosol Mouse Model of Mycobacterium avium Infection. Lanoix, JP., Joseph, C., Peltier, F., et al.[2021]

Clofazimine shows varying minimal inhibitory concentrations (MICs) against different strains of nontuberculous mycobacteria, with lower MICs (≤ 0.25 mg/L) being associated with a higher likelihood of achieving negative sputum culture conversion in patients.

In a study of 20 patients treated with clofazimine, 40% achieved negative culture conversion, particularly those with MIC values ≤ 0.25 mg/L, suggesting that clofazimine could be an effective treatment option for NTM-PD in cases with lower MICs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Minimal Inhibitory Concentration of Clofazimine Among Clinical Isolates of Nontuberculous Mycobacteria and Its Impact on Treatment Outcome. Kwak, N., Whang, J., Yang, JS., et al.[2021]

Inhaled delivery of micronized clofazimine (CFZ) significantly increases drug concentrations in the lungs and provides faster bactericidal effects against tuberculosis compared to oral administration, as shown in a study with BALB/c mice.

The formulation of CFZ is stable and resistant to degradation, making it a suitable option for treating TB in low-resource settings where cold-chain storage is challenging.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Respirable Clofazimine Particles Produced by Air Jet Milling Technique Are Efficacious in Treatment of BALB/c Mice with Chronic Mycobacterium tuberculosis Infection. Brunaugh, AD., Walz, A., Warnken, Z., et al.[2023]

Clofazimine demonstrated strong in vitro activity against 80 isolates of rapidly growing nonchromogenic mycobacteria, inhibiting 96% of the strains at concentrations of 1 microgram/ml or less.

The drug shows potential efficacy specifically against Mycobacterium fortuitum and M. chelonae, suggesting it could be a valuable treatment option for infections caused by these bacteria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In vitro activity of clofazimine against rapidly growing nonchromogenic mycobacteria. Ausina, V., Condom, MJ., Mirelis, B., et al.[2021]

A novel inhaled formulation of clofazimine was tested in canines over 28 days, showing significant drug retention in lung tissue and maintaining concentrations well above the minimum inhibitory concentration (MIC) for nontuberculous mycobacteria (NTM).

This inhalation method may reduce systemic toxicity associated with traditional oral or parenteral clofazimine treatments, providing a more effective and safer option for managing NTM infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clofazimine Inhalation Suspension Demonstrates Promising Toxicokinetics in Canines for Treating Pulmonary Nontuberculous Mycobacteria Infection. Kunkel, M., Doyle-Eisele, M., Kuehl, P., et al.[2023]

Clofazimine was found to be a safe and reasonably tolerated treatment option for patients with nontuberculous mycobacterial (NTM) infections, with 50% of patients showing negative NTM cultures within 12 months of treatment.

In a study of 112 patients, including both pediatric and adult individuals with cystic fibrosis and non-cystic fibrosis, clofazimine demonstrated clinical efficacy, particularly in those with refractory disease, suggesting it could be a valuable alternative in NTM treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Effectiveness of Clofazimine for Primary and Refractory Nontuberculous Mycobacterial Infection. Martiniano, SL., Wagner, BD., Levin, A., et al.[2018]

Clofazimine has shown effectiveness against various nontuberculous mycobacteria, making it a potential treatment option for infections like Mycobacterium avium.

In a unique case, a woman with cystic fibrosis and a macrolide-resistant Mycobacterium avium infection was successfully treated with clofazimine administered through a gastrostomy tube, highlighting a novel method of delivery for this medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Novel Administration of Clofazimine for the Treatment of Mycobacterium avium Infection. Valinetz, E., Stankiewicz Karita, H., Pottinger, PS., et al.[2022]

In a study testing 14 compounds for their effectiveness against Mycobacterium intracellulare, only clofazimine and chaulmoogric acid demonstrated significant activity.

Clofazimine, known for its minimal side effects, shows promise as a potential treatment for M. intracellulare infections, warranting further research.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antimycobacterial activity of some potential chemotherapeutic compounds. Damle, P., McClatchy, JK., Gangadharam, PR., et al.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06418711

NCT06418711 | ICoN-1 Phase 3 Study of the Efficacy and ... 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, ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9933692/

Clofazimine Inhalation Suspension Demonstrates ... Clofazimine inhalation suspension may provide an effective therapy for the treatment of NTM infections through direct delivery of antibiotic to the lungs.

3. liebertpub.com liebertpub.com/doi/10.1177/19412711251370275

Clofazimine Inhalation Suspension: A Novel Formulation ... Safety and effectiveness of clofazimine in nontuberculous mycobacterial lung disease. Can J Respir Crit Care Sleep Med 2018;2(2):72–77. Go ...

4. investors.mannkindcorp.com investors.mannkindcorp.com/news-releases/news-release-details/mannkinds-inhaled-clofazimine-will-advance-adaptive-phase-23

MannKind's Inhaled Clofazimine Will Advance to an ... Paper published on clofazimine inhalation suspension demonstrates promising tolerability and toxicokinetics for treating pulmonary NTM infection. DANBURY ...

5. clinicaltrials.ucsf.edu clinicaltrials.ucsf.edu/trial/NCT06418711

ICoN-1 Phase 3 Study of the Efficacy and Safety of Treatment ... 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, ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/41005977/

Clofazimine Inhalation Suspension: A Novel Formulation ... The objective of this study was to evaluate the pharmacokinetic and safety profiles and proposed dosing regimen of Clofazimine Inhalation ...

7. journals.asm.org journals.asm.org/doi/10.1128/aac.01144-22

Clofazimine Inhalation Suspension Demonstrates Promising ... Clofazimine inhalation suspension may provide an effective therapy for the treatment of NTM infections through direct delivery of antibiotic to the lungs.