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Comparison of Two- Versus Three-antibiotic Therapy for Pulmonary Mycobacterium Avium Complex Disease (MAC2v3)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03672630
Recruitment Status : Recruiting
First Posted : September 14, 2018
Last Update Posted : February 27, 2020
Sponsor:
Collaborators:
Patient-Centered Outcomes Research Institute
National Jewish Health
The University of Texas Health Science Center at Tyler
University Health Network, Toronto
New York University
Medical University of South Carolina
Mayo Clinic
Georgetown University
University of Chicago
Louisiana State University Health Sciences Center in New Orleans
University of California, San Diego
Stanford University
University of Kansas
Vancouver Clinic
University of California, San Francisco
University of Washington
Johns Hopkins University
University of Miami
Emory University
University of Iowa
University of North Carolina
Yale University
Temple University
Loma Linda University
Columbia University
University of Wisconsin, Madison
Information provided by (Responsible Party):
Kevin Winthrop, Oregon Health and Science University

Tracking Information
First Submitted Date  ICMJE September 11, 2018
First Posted Date  ICMJE September 14, 2018
Last Update Posted Date February 27, 2020
Actual Study Start Date  ICMJE February 22, 2019
Estimated Primary Completion Date February 28, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 30, 2018)
  • Acid-fast bacilli (AFB) culture negativity [ Time Frame: 12 months post randomization ]
    Two consecutive negative AFB cultures by 12 months post randomization without reversion to positive
  • Therapy completion [ Time Frame: 12 months post randomization ]
    The proportion of patients who complete 12 months of therapy on their assigned regimen with "satisfactory adherence". "Satisfactory adherence" is defined as taking 80% of their prescribed doses/not missing more than 75 days of treatment.
Original Primary Outcome Measures  ICMJE
 (submitted: September 13, 2018)
  • Culture conversion [ Time Frame: 12 months post randomization ]
    Expectorated or induced sputum will be processed for acid fast bacilli stain/acid fast bacterial culture using standard methodology in clinical practice. Culture conversion is defined as two consecutive cultures negative for mycobacterium avium complex by 12 months post randomization without reversion to positive
  • Therapy completion [ Time Frame: 12 months post randomization ]
    The proportion of patients who complete 12 months of therapy on their assigned regimen with "satisfactory adherence". "Satisfactory adherence" is defined as taking 80% of their prescribed doses/not missing more than 75 days of treatment.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 13, 2018)
  • QOL-B Respiratory Symptoms Score [ Time Frame: 12 months post randomization ]
    Quality of Life-Bronchiectasis (QOL-B) with NTM module The QOL-B is a self-administered questionnaire that has been validated in patients with bronchiectasis. The questionnaire measures 8 separate domains: Physical Functioning, Role Functioning, Vitality, Emotional Functioning, Social Functioning, Treatment Burden, Health Perceptions, and Respiratory Symptoms.
  • NTM Symptoms Score [ Time Frame: 12 months post randomization ]
    Quality of Life-Bronchiectasis (QOL-B) with NTM module The QOL-B is a self-administered questionnaire that has been validated in patients with bronchiectasis. The NTM module includes 4 additional domains: Eating Problems, Body Image, Digestive Symptoms, and NTM Symptoms. No total score is calculated.
  • Fatigue AE proportion [ Time Frame: Cumulative to 12 months ]
    Self-report, Moderate or worse
  • Gastrointestinal AE proportion [ Time Frame: up to 12 months ]
    Self-report, Moderate or worse: Nausea, diarrhea, decreased appetite, OR abdominal pain
  • Liver AE proportion [ Time Frame: up to 12 months ]
    Laboratory grade 2 or higher abnormality
  • Macrolide resistance [ Time Frame: 12 months post randomization ]
    Susceptibility at last positive culture
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Comparison of Two- Versus Three-antibiotic Therapy for Pulmonary Mycobacterium Avium Complex Disease
Official Title  ICMJE Comparison of Two- Versus Three-antibiotic Therapy for Pulmonary Mycobacterium Avium Complex Disease
Brief Summary NTM therapy consists of a multi-drug macrolide based regimen for 18-24 months. Treated patients frequently experience debilitating side effects, and many patients delay the start of antibiotic treatment due to these risks. Common side effects include nausea, diarrhea, and fatigue, and rare but serious toxicities include ocular toxicity, hearing loss, and hematologic toxicity. To date, most of the evidence underlying the current treatment recommendations has come from observational studies in which either a macrolide has been combined with rifampin and ethambutol, or in some cases combined with ethambutol alone. The proposed study will answer whether a third drug is necessary or whether taking two drugs can increase tolerability without a substantial loss of efficacy.
Detailed Description Mycobacterium avium complex (MAC) are a subset of nontuberculous mycobacteria (NTM), environmental bacteria that can cause chronic, debilitating pulmonary disease, primarily affecting those over age 60. The goals of treatment are to improve symptoms, stop disease progression, and clear the infection. We propose to address a longstanding controversy in the therapy of pulmonary MAC disease, whether patients must take three antibiotics concomitantly, or if two are sufficient. The study is a multicenter randomized pragmatic clinical trial to compare azithromycin + ethambutol (2-drug therapy) vs. azithromycin + ethambutol + rifampin (3-drug therapy) for non-cavitary pulmonary MAC disease. All clinical outcomes will be considered standard of care and abstracted from clinical records. Therapy changes and adverse events will be recorded at routine visits. Health-related quality of life (HRQoL) and self-reported toxicity will be captured centrally in a web-based database, and CT scans will be read centrally. Co-primary outcomes are culture conversion and tolerability of treatment. The primary analysis for culture conversion will be conducted as a per-protocol non-inferiority analysis, and the primary analysis for tolerability will be conducted as an intention-to-treat superiority analysis.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Mycobacterium Avium Complex
  • Nontuberculous Mycobacterium Infection
Intervention  ICMJE
  • Drug: Azithromycin
    Azithromycin 500 MG Oral Tablet [ZITHROMAX]
    Other Name: Zithromax
  • Drug: Ethambutol
    Ethambutol 25 mg/kg [MYAMBUTOL]
    Other Name: Myambutol
  • Drug: Rifampin
    Rifampin 600 MG [RIFADIN]
    Other Name: Rifadin
Study Arms  ICMJE
  • Active Comparator: 2-drug regimen
    This arm is a 3 time per week (TIW) treatment regimen that includes azithromycin 500 mg po + ethambutol 25 mg/kg Treatment changes are at the discretion of the treating physician and patient. Where possible, changes in dosing or frequency that allow the patient to continue taking the assigned drugs during the 12 months study period are preferred.
    Interventions:
    • Drug: Azithromycin
    • Drug: Ethambutol
  • Active Comparator: 3-drug regimen
    This arm is a 3 time per week (TIW) treatment regimen that includes azithromycin 500 mg po + ethambutol 25 mg/kg + rifampin 600 mg Treatment changes are at the discretion of the treating physician and patient. Where possible, changes in dosing or frequency that allow the patient to continue taking the assigned drugs during the 12 months study period are preferred.
    Interventions:
    • Drug: Azithromycin
    • Drug: Ethambutol
    • Drug: Rifampin
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 13, 2018)
500
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 28, 2023
Estimated Primary Completion Date February 28, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Culture positive pulmonary MAC meeting ATS/IDSA disease criteria
  • Age over 18 years
  • Ability to provide informed consent

Exclusion Criteria:

  • Fibrocavitary disease
  • Planned surgery for MAC disease
  • Prior multi-drug therapy for pulmonary NTM
  • Cystic fibrosis
  • HIV
  • History of solid organ or hematologic transplant
  • Significant drug-drug interaction not clinically manageable in the opinion of the investigator
  • Contraindication to any component of the study treatment regimen
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Andie Hendrick 503-494-2136 hendrmic@ohsu.edu
Contact: Megan E Wardrop, MS 503-346-3752 wardrop@ohsu.edu
Listed Location Countries  ICMJE Canada,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03672630
Other Study ID Numbers  ICMJE 18819
PCS-2017C2-7764 ( Other Grant/Funding Number: PCORI )
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: A Full Data Package will be made available in a PCORI-designated repository. The Full Data Package includes the Analyzable Data Set, Full Protocol, metadata, data dictionary, full statistical analysis plan (including all amendments and all documentation for additional work processes), and analytic code from the PCORI-funded research project. The Analyzable Dataset includes a final cleaned and locked data set that contains all the data used in conducting the analyses reported in the PCORI Final Research Report and is de-identified in accordance with the HIPAA Privacy Rule (45 C.F.R. § 164.514(b)).
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Analytic Code
Time Frame: The dataset will be available after completion of the study and publication of results.
Access Criteria: Third party data requests will be reviewed by a committee, and approved requests will require a DUA.
Responsible Party Kevin Winthrop, Oregon Health and Science University
Study Sponsor  ICMJE Kevin Winthrop
Collaborators  ICMJE
  • Patient-Centered Outcomes Research Institute
  • National Jewish Health
  • The University of Texas Health Science Center at Tyler
  • University Health Network, Toronto
  • New York University
  • Medical University of South Carolina
  • Mayo Clinic
  • Georgetown University
  • University of Chicago
  • Louisiana State University Health Sciences Center in New Orleans
  • University of California, San Diego
  • Stanford University
  • University of Kansas
  • Vancouver Clinic
  • University of California, San Francisco
  • University of Washington
  • Johns Hopkins University
  • University of Miami
  • Emory University
  • University of Iowa
  • University of North Carolina
  • Yale University
  • Temple University
  • Loma Linda University
  • Columbia University
  • University of Wisconsin, Madison
Investigators  ICMJE
Study Director: Emily Henkle, PhD, MPH Oregon Health and Science University
Principal Investigator: Kevin L Winthrop, MD, MPH Oregon Health and Science University
PRS Account Oregon Health and Science University
Verification Date February 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP