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

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ClinicalTrials.gov Identifier: NCT02968212
Recruitment Status : Recruiting
First Posted : November 18, 2016
Last Update Posted : September 28, 2018
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
National Jewish Health
The University of Texas Health Science Center at Tyler
National Institute of Allergy and Infectious Diseases (NIAID)
Information provided by (Responsible Party):
Kevin Winthrop, Oregon Health and Science University

Brief 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


Condition or disease Intervention/treatment Phase
Mycobacterium Avium Complex Drug: Clofazimine Other: sugar pill Phase 2

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  (Clinical Trial)
Estimated Enrollment : 102 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Phase 2 Study of Clofazimine for the Treatment of Pulmonary Mycobacterium Avium Disease
Actual Study Start Date : April 11, 2017
Estimated Primary Completion Date : December 2021
Estimated Study Completion Date : September 2022

Resource links provided by the National Library of Medicine


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 Name: 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 Name: placebo




Primary Outcome Measures :
  1. Change from Baseline sputum culture at 24 weeks [ Time Frame: Sputum examined for culture change from Baseline 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.


Secondary Outcome Measures :
  1. Change from Baseline 6 Minute Walk Test at 24 weeks [ Time Frame: 6 Minute Walk Test results examined for change from Baseline at 24 weeks ]
    Walking distance achieved in 6 minutes is assessed

  2. Change from Baseline St. George Respiratory Questionnaire (SGRQ) at 24 weeks [ Time Frame: SGRQ results examined for change from Baseline at 24 weeks ]
    Self-administered questionnaire assessing health-related quality of life in subjects with chronic pulmonary disease by evaluating 3 health domains: symptoms, activity, and impacts.

  3. Change from Baseline Quality of Life-Bronchiectasis (QOL-B) with NTM module at 24 weeks [ Time Frame: QOL-B results examined for change from Baseline 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.

  4. Change from Baseline CT scan at 24 weeks [ Time Frame: CT scan examined for change from Baseline at 24 weeks ]
    CT scans will be computationally evaluated using custom software to provide volumetric assessment of NTM-associated abnormalities.

  5. Change from Baseline semi-quantitative sputum acid fast smear culture at 24 weeks [ Time Frame: semi-quantitative sputum acid fast smear culture examined for change from Baseline 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.

  6. Change from Baseline Spirometry at 24 weeks [ Time Frame: Spirometry with FEV1/FVC ratio examined for change from Baseline at 24 weeks ]
    Mean change in pulmonary function parameters as measured by %predicted FEV1 and FVC

  7. Change from Baseline Erythrocyte Sedimentation Rate at 24 weeks [ Time Frame: Erythrocyte Sedimentation Rate examined for change from Baseline at 24 weeks ]
    Detecting change in Inflammatory markers

  8. Change from Baseline C-Reactive Protein levels at 24 weeks [ Time Frame: C-Reactive Protein levels examined for change from Baseline at 24 weeks ]
    Detecting change in Inflammatory markers

  9. Number of Adverse Events [ Time Frame: Number of Patient-reported and Investigator-reported Adverse Events at 24 weeks ]
    Comparison of experienced adverse events between the two study groups

  10. Change from Baseline QT interval at 24 weeks [ Time Frame: QT interval examined for change from Baseline at 24 weeks ]
    A 12-lead ECG will be conducted, and the QT interval calculated using Fridericia's formula: QTC = QT / RR 1/3

  11. Change from Baseline blood serum chemistry at week 24 [ Time Frame: blood serum chemistry examined for change from Baseline at 24 weeks ]
    Detecting changes in liver ALT and AST levels

  12. Change from Baseline complete blood count at week 24 [ Time Frame: complete blood count examined for change from Baseline at 24 weeks ]
    Detecting changes in complete blood count

  13. Change from Baseline Minimal Inhibitory Concentration of MAC isolates in vitro at week 24 [ Time Frame: Minimal Inhibitory Concentration of MAC isolates in vitro examined for change from Baseline at 24 weeks ]
    Detecting change in MAC isolates sensitivity to clofazimine



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02968212


Contacts
Contact: Megan E Wardrop, MS 503-346-3752 wardrop@ohsu.edu
Contact: Emily Henkle, PhD, MPH 503-494-6226 henkle@ohsu.edu

Locations
United States, Colorado
National Jewish Health Recruiting
Denver, Colorado, United States, 80206
Contact: Charles L Daley, MD         
Principal Investigator: Charles L Daley, MD         
United States, Maryland
National Heart, Lung and Blood Institute Not yet recruiting
Bethesda, Maryland, United States, 20814
Contact: Kenneth N Olivier, MD, MPH         
United States, Oregon
Oregon Health & Science University Recruiting
Portland, Oregon, United States, 97239
Contact: Megan E Wardrop, MS         
Contact: Emily Henkle, PhD, MPH         
Principal Investigator: Kevin L Winthrop, MD, MPH         
United States, Texas
University of Texas Health Science Center Recruiting
Tyler, Texas, United States, 75708
Contact: David E Griffith, MD         
Principal Investigator: David E Griffith, MD         
Sponsors and Collaborators
Oregon Health and Science University
National Heart, Lung, and Blood Institute (NHLBI)
National Jewish Health
The University of Texas Health Science Center at Tyler
National Institute of Allergy and Infectious Diseases (NIAID)

Responsible Party: Kevin Winthrop, Associate Professor, Oregon Health and Science University
ClinicalTrials.gov Identifier: NCT02968212     History of Changes
Other Study ID Numbers: FD-R-5401
First Posted: November 18, 2016    Key Record Dates
Last Update Posted: September 28, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Kevin Winthrop, Oregon Health and Science University:
Mycobacterium avium Complex
Clofazimine

Additional relevant MeSH terms:
Mycobacterium Infections
Mycobacterium avium-intracellulare Infection
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Mycobacterium Infections, Nontuberculous
Clofazimine
Anti-Inflammatory Agents
Leprostatic Agents
Anti-Bacterial Agents
Anti-Infective Agents