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

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

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

Study Overview

• Status: Recruiting
• Conditions: Mycobacterium Avium Complex
• Intervention / Treatment: Drug: Clofazimine; Other: sugar pill

Detailed 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.

• Study Type: Interventional
• Enrollment (Estimated): 102
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Naomi DeBacker; Phone Number: 503-346-3435; Email: debacken@ohsu.edu
• Study Contact Backup: Name: Daniel Bouchat; Phone Number: 503-494-2568; Email: johdanie@ohsu.edu

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80206
      • Completed
      • National Jewish Health
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Withdrawn
      • Georgetown University
  • Florida
    • Tampa, Florida, United States, 33620
      • Recruiting
      • University of South Florida
      • Contact: Tatyana Harris, MBA-MHA, DHA; Phone Number: 813-250-2392; Email: trharris1@usf.edu
      • Principal Investigator: W. Dwight Miller, MD, MS
  • Illinois
    • Chicago, Illinois, United States, 60637
      • Completed
      • University of Chicago
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70803
      • Recruiting
      • Louisiana State University
      • Principal Investigator: Judd Shellito, MD
      • Contact: Olivia Rohert; Phone Number: 504-568-2248; Email: orohre@lsuhsc.edu
  • Maryland
    • Bethesda, Maryland, United States, 20814
      • Active, not recruiting
      • National Heart, Lung and Blood Institute
  • Oregon
    • Portland, Oregon, United States, 97239
      • Recruiting
      • Oregon Health & Science University
      • Contact: Gina Megson, MPH; Phone Number: (503) 494-2565; Email: megson@ohsu.edu
      • Contact: Naomi DeBacker; Phone Number: 503-346-3435; Email: debacken@ohsu.edu
      • Principal Investigator: Kevin L Winthrop, MD, MPH
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Withdrawn
      • Temple University Hospital
  • Texas
    • Tyler, Texas, United States, 75708
      • Recruiting
      • University of Texas Health Science Center
      • Principal Investigator: Pamela J McShane, MD
      • Contact: Alexis Hester, MA; Phone Number: 903-877-7860; Email: alexis.hester@uttyler.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: clofazimine; Participants receive lamprene	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 Names: Lamprene
Placebo Comparator: sugar pill; Participants receive placebo	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.; Other Names: placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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
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
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
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
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
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
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
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
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

Collaborators and Investigators

• Sponsor: Oregon Health and Science University
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); National Heart, Lung, and Blood Institute (NHLBI); University of South Florida; University of Chicago; Temple University; The University of Texas Health Science Center at Tyler; National Jewish Health
• Investigators: Principal Investigator: Kevin Winthrop, MD, Oregon Health and Science University

Study record dates

Study Major Dates

• Study Start (Actual): April 11, 2017
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): April 1, 2025

Study Registration Dates

• First Submitted: November 10, 2016
• First Submitted That Met QC Criteria: November 16, 2016
• First Posted (Estimated): November 18, 2016

Study Record Updates

• Last Update Posted (Actual): March 27, 2024
• Last Update Submitted That Met QC Criteria: March 25, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Mycobacterium avium Complex; Clofazimine
• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections, Nontuberculous; Mycobacterium Infections; Mycobacterium avium-intracellulare Infection; Anti-Infective Agents; Anti-Inflammatory Agents; Anti-Bacterial Agents; Leprostatic Agents; Clofazimine
• Other Study ID Numbers: FD-R-5401

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No