Clofazimine in the Treatment of Pulmonary Mycobacterium Avium Complex (MAC)

Mycobacterium Avium Complex Clinical Trial

Official title:

Phase 2 Study of Clofazimine for the Treatment of Pulmonary Mycobacterium Avium Disease

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02968212
• Other study ID #: FD-R-5401
• Status: Recruiting
• Phase: Phase 2
• Start date: April 11, 2017
• Est. completion date: April 2025

Study information

• Verified date: March 2024
• Source: Oregon Health and Science University
• Contact: Naomi DeBacker
• Phone: 503-346-3435
• Email: debacken[@]ohsu.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the clinical effectiveness and safety of clofazimine when used to treat Mycobacteria avium complex (MAC) lung disease.

Funding Source - FDA OOPD

Description:

Clofazimine is an orphan antibiotic drug that is no longer available through pharmacies in the United States. It is approved for the treatment of Mycobacterium leprae (leprosy) infections. Clofazimine has been used for many years off-label against other Mycobacterium, including Mycobacteria avium complex (MAC) lung disease, an increasingly prevalent infection in older Americans. The U.S. Food and Drug Administration currently oversees clofazimine use to treat MAC lung disease through a special investigational drug access program. However, to date, there is little understanding of the benefits and risks of clofazimine when used to treat MAC lung disease. Accordingly, the investigators have developed a randomized, placebo-controlled clinical trial to assess the clinical efficacy and safety of clofazimine. To be eligible, participants must have MAC lung disease, positive sputum cultures for MAC, and not currently taking antibiotics for MAC. Eligible participants (102 total enrolled) will be randomly given either clofazimine or placebo for 6 months, and followed closely by their treating physician. The percentage of participants who become culture negative in each group will be compared, as it is suspected that participants treated with clofazimine will be more likely to become culture negative. The safety of clofazimine will be measured as well as other potential benefits of the therapy including changes in lung function and quality of life.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 102
• Est. completion date: April 2025
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• At least 2 positive MAC sputum cultures in the last 12 months with at least one obtained within 12 weeks prior to randomization

• Meet ATS/IDSA 2007 pulmonary disease criteria

• Adult males and females age 18 or over

• Ability to provide informed consent for the use of study drug

Exclusion Criteria:

• Any patient who is unwilling or unable to provide consent or to comply with this protocol

• Cavitary NTM disease

• Patients who are currently taking or within the prior 12 weeks received any of the following: bedaquiline, or any component of ATS/IDSA multi-drug recommended therapy (macrolide, ethambutol, rifampin) for MAC

• Current usage of inhaled amikacin, tobramycin, or gentamicin

• In the judgment of the investigator, the patient is not a candidate for observation (e.g. severe symptoms, extensive disease burden) but rather should be treated with standard multi-drug therapy

• Prior use of clofazimine that has resulted in an allergy to clofazimine or a severe adverse reaction

• Current usage of medications associated with QT prolongation (see Appendix C for full list of prohibited concomitant medications)

• Corrected QT (QTc) interval on electrocardiogram (ECG) > 470 ms for females or 450 ms for males, calculated using Fridericia's formula60,61

• Advanced lung disease (FEV<30%)

• HIV

• Active pulmonary tuberculosis requiring treatment at screening

• Active pulmonary malignancy or chemotherapy or radiation within 1 year of screening

• Use of chronic systemic corticosteroids at doses of 15 mg/day for more than 12 weeks

• Prior lung or other solid organ transplant

• Pregnancy, or breastfeeding that will continue during treatment

Related Conditions & MeSH terms

• Mycobacterium Avium Complex
• Mycobacterium avium-intracellulare Infection
• Mycobacterium Infections

Intervention

Drug:
• Clofazimine
All participants in the experimental/treatment arm on this protocol will take a loading dose of 200 mg daily in soft capsule form of clofazimine for 16 weeks, dropping to 100 mg daily for the next 8 weeks.

Other:
• sugar pill
All participants in the placebo arm on this protocol will take placebo in soft capsule form daily dropping to a smaller dose after 16 weeks to mirror the treatment arm dosing.

Locations

Country	Name	City	State
United States	Louisiana State University	Baton Rouge	Louisiana
United States	National Heart, Lung and Blood Institute	Bethesda	Maryland
United States	University of Chicago	Chicago	Illinois
United States	National Jewish Health	Denver	Colorado
United States	Temple University Hospital	Philadelphia	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	University of South Florida	Tampa	Florida
United States	University of Texas Health Science Center	Tyler	Texas
United States	Georgetown University	Washington	District of Columbia

Sponsors (8)

Lead Sponsor	Collaborator
Oregon Health and Science University	National Heart, Lung, and Blood Institute (NHLBI), National Institute of Allergy and Infectious Diseases (NIAID), National Jewish Health, Temple University, The University of Texas Health Science Center at Tyler, University of Chicago, University of South Florida

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from Baseline sputum culture at 24 weeks	sputum will be processed for acid fast bacilli stain/acid fast bacterial culture. A semi-quantitative assessment will be made by colony count for patients.	Sputum examined for culture change from Baseline at 24 weeks
Secondary	Change from Baseline 6 Minute Walk Test at 24 weeks	Walking distance achieved in 6 minutes is assessed	6 Minute Walk Test results examined for change from Baseline at 24 weeks
Secondary	Change from Baseline PROMIS Fatigue 7a short form questionnaire at 24 weeks	Self-administered questionnaire assessing a range of self-reported symptoms over the past seven days, from mild subjective feelings of tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that likely decreases one's ability to execute daily activities and function normally in family or social roles. Fatigue is divided into the experience of fatigue (frequency, duration, and intensity) and the impact of fatigue on physical, mental, and social activities.	PROMIS Fatigue 7a short form results examined for change from Baseline at 24 weeks
Secondary	Change from Baseline Quality of Life-Bronchiectasis (QOL-B) with NTM module at 24 weeks	Self-administered questionnaire measuring 8 separate domains: Physical Functioning, Role Functioning, Vitality, Emotional Functioning, Social Functioning, Treatment Burden, Health Perceptions, and Respiratory Symptoms.	QOL-B results examined for change from Baseline at 24 weeks
Secondary	Change from Baseline CT scan at 24 weeks	CT scans will be computationally evaluated using custom software to provide volumetric assessment of NTM-associated abnormalities.	CT scan examined for change from Baseline at 24 weeks
Secondary	Change from Baseline semi-quantitative sputum acid fast smear culture at 24 weeks	sputum will be processed for acid fast bacilli stain/acid fast bacterial culture. A semi-quantitative assessment will be made by colony count for patients.	semi-quantitative sputum acid fast smear culture examined for change from Baseline at 24 weeks
Secondary	Change from Baseline Spirometry at 24 weeks	Mean change in pulmonary function parameters as measured by %predicted FEV1 and FVC	Spirometry with FEV1/FVC ratio examined for change from Baseline at 24 weeks
Secondary	Change from Baseline Erythrocyte Sedimentation Rate at 24 weeks	Detecting change in Inflammatory markers	Erythrocyte Sedimentation Rate examined for change from Baseline at 24 weeks
Secondary	Change from Baseline C-Reactive Protein levels at 24 weeks	Detecting change in Inflammatory markers	C-Reactive Protein levels examined for change from Baseline at 24 weeks
Secondary	Number of Adverse Events	Comparison of experienced adverse events between the two study groups	Number of Patient-reported and Investigator-reported Adverse Events at 24 weeks
Secondary	Change from Baseline QT interval at 24 weeks	A 12-lead ECG will be conducted, and the QT interval calculated using Fridericia's formula: QTC = QT / RR 1/3	QT interval examined for change from Baseline at 24 weeks
Secondary	Change from Baseline blood serum chemistry at week 24	Detecting changes in liver ALT and AST levels	blood serum chemistry examined for change from Baseline at 24 weeks
Secondary	Change from Baseline complete blood count at week 24	Detecting changes in complete blood count	complete blood count examined for change from Baseline at 24 weeks
Secondary	Change from Baseline Minimal Inhibitory Concentration of MAC isolates in vitro at week 24	Detecting change in MAC isolates sensitivity to clofazimine	Minimal Inhibitory Concentration of MAC isolates in vitro examined for change from Baseline at 24 weeks