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

March 25, 2024 updated by: Kevin Winthrop
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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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

Interventional

Enrollment (Estimated)

500

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5T2S8
        • Recruiting
        • University Health Network
        • Contact:
        • Principal Investigator:
          • Theodore Marras, MD
        • Contact:
  • United States
    • California
      • Loma Linda, California, United States, 92354
        • Active, not recruiting
        • Loma Linda University Medical Center
      • San Diego, California, United States, 92103
        • Recruiting
        • University of California, San Diego
        • Principal Investigator:
          • Wael ElMaraachli, MD
        • Contact:
      • San Francisco, California, United States, 94110
        • Recruiting
        • University of California, San Francisco
        • Principal Investigator:
          • Payam Nahid, MD, MPH
        • Contact:
        • Contact:
        • Sub-Investigator:
          • Shoshana Zha, MD, PhD
      • Stanford, California, United States, 94305
        • Recruiting
        • Stanford University
        • Principal Investigator:
          • Steven Ruoss, MD
        • Contact:
    • Colorado
      • Denver, Colorado, United States, 80206
        • Recruiting
        • National Jewish Health
        • Principal Investigator:
          • Charles L Daley, MD
        • Contact:
    • Connecticut
      • New Haven, Connecticut, United States, 06520
        • Withdrawn
        • Yale University
    • District of Columbia
      • Washington, District of Columbia, United States, 20007
        • Withdrawn
        • Georgetown University
    • Florida
      • Miami, Florida, United States, 33136
        • Terminated
        • University of Miami
      • Tampa, Florida, United States, 33612
        • Recruiting
        • Tampa VA Medical Center
        • Contact:
        • Contact:
        • Principal Investigator:
          • Anthony Canella, MD
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Recruiting
        • Emory University
        • Principal Investigator:
          • Colin Swenson, MD
        • Contact:
    • Hawaii
      • Honolulu, Hawaii, United States, 96817
        • Recruiting
        • Kaiser Permanente Hawaii
        • Principal Investigator:
          • Janet Myers, MD
        • Contact:
    • Iowa
      • Iowa City, Iowa, United States, 52242
        • Active, not recruiting
        • University of Iowa
    • Kansas
      • Kansas City, Kansas, United States, 66160
        • Terminated
        • University of Kansas
    • Louisiana
      • New Orleans, Louisiana, United States, 70112
        • Recruiting
        • Louisina State University
        • Principal Investigator:
          • Judd Shellito, MD
        • Contact:
        • Sub-Investigator:
          • Shelby MacRae, MD
        • Sub-Investigator:
          • Juzar Ali, MD
        • Sub-Investigator:
          • Amy Wolfe, MD
    • Maryland
      • Baltimore, Maryland, United States, 21224
        • Recruiting
        • Johns Hopkins University
        • Contact:
        • Principal Investigator:
          • Elisa Ignatius, MD
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Recruiting
        • Mayo Clinic
        • Principal Investigator:
          • Timothy Aksamit, MD
        • Contact:
    • New York
      • Manhasset, New York, United States, 11030
        • Recruiting
        • Northwell Health
        • Principal Investigator:
          • Lisa Hayes, MD
        • Contact:
        • Contact:
        • Sub-Investigator:
          • Marcia Epstein, MD
      • New York, New York, United States, 10032
        • Recruiting
        • Columbia University Medical Center
        • Principal Investigator:
          • Angela Dimango, MD
        • Contact:
      • New York, New York, United States, 10016
        • Recruiting
        • New York University
        • Contact:
        • Principal Investigator:
          • Doreen Addrizzo-Harris, MD
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27599
        • Recruiting
        • University of North Carolina
        • Contact:
        • Principal Investigator:
          • Daniels Leigh Anne, MD, MPH
        • Sub-Investigator:
          • Kenneth Olivier, MD, MPH
        • Sub-Investigator:
          • Kunal Jakharia, MD
        • Sub-Investigator:
          • Kunal Patel, MD, PhD
    • Oregon
      • Portland, Oregon, United States, 97239
        • Recruiting
        • Oregon Health & Science University
        • Contact:
        • Principal Investigator:
          • Kevin Winthrop, MD, MPH
        • Contact:
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19140
        • Recruiting
        • Temple University
        • Principal Investigator:
          • Daniel Salerno, MD, MS
        • Contact:
    • South Carolina
      • Charleston, South Carolina, United States, 29425
        • Recruiting
        • Medical University of South Carolina
        • Principal Investigator:
          • Patrick Flume, MD
        • Contact:
    • Texas
      • Tyler, Texas, United States, 75708
        • Recruiting
        • University of Texas Health Science Center
        • Principal Investigator:
          • Pamela J McShane, MD
        • Contact:
    • Washington
      • Seattle, Washington, United States, 98104
        • Terminated
        • University of Washington
      • Vancouver, Washington, United States, 98664
        • Recruiting
        • Vancouver Clinic
        • Principal Investigator:
          • Nicholas Wysham, MD
        • Contact:
    • Wisconsin
      • Madison, Wisconsin, United States, 53705
        • Recruiting
        • University of Wisconsin School of Medicine and Public Health
        • Principal Investigator:
          • Chris Saddler, MD
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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
  • Patients who have cumulatively taken 6 weeks or more of multi-drug antimicrobial treatment for MAC
  • Patients who are currently taking or have taken multi-drug antimicrobial treatment for NTM within the prior 30 days
  • Diagnosis of Cystic fibrosis
  • Diagnosis of 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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.
Drug: Azithromycin
Azithromycin 500 MG Oral Tablet [ZITHROMAX]
Other Names:
  • Zithromax
Drug: Ethambutol
Ethambutol 25 mg/kg [MYAMBUTOL]
Other Names:
  • Myambutol
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.
Drug: Azithromycin
Azithromycin 500 MG Oral Tablet [ZITHROMAX]
Other Names:
  • Zithromax
Drug: Ethambutol
Ethambutol 25 mg/kg [MYAMBUTOL]
Other Names:
  • Myambutol
Drug: Rifampin
Rifampin 600 MG [RIFADIN]
Other Names:
  • Rifadin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
12 months post randomization
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.
12 months post randomization

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
12 months post randomization
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.
12 months post randomization
PROMIS Fatigue 7a short form score
Time Frame: 12 months post randomization
PROMIS Fatigue 7a short form score The PROMIS Fatigue item banks assess 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. Each question has five response options ranging in value from one to five. To find the total raw score for a short form with all questions answered, sum the values of the response to each question. The lowest possible raw score (indicating the highest subjective level of fatigue) is 7; and the highest possible raw score (indicating the lowest subjective level of fatigue) is 35.
12 months post randomization
Fatigue AE proportion
Time Frame: Cumulative to 12 months
Self-report, Moderate or worse
Cumulative to 12 months
Gastrointestinal AE proportion
Time Frame: up to 12 months
Self-report, Moderate or worse: Nausea, diarrhea, decreased appetite, OR abdominal pain
up to 12 months
Liver AE proportion
Time Frame: up to 12 months
Laboratory grade 2 or higher abnormality
up to 12 months
Macrolide resistance
Time Frame: 12 months post randomization
Susceptibility at last positive culture
12 months post randomization

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Kevin Winthrop

Collaborators

Patient-Centered Outcomes Research Institute
Medical University of South Carolina
Johns Hopkins University
University Health Network, Toronto
Mayo Clinic
University of California, San Diego
University of Miami
Northwell Health
New York University
Columbia University
University of Iowa
University of Wisconsin, Madison
Emory University
University of Washington
University of California, San Francisco
Stanford University
Temple University
Loma Linda University
Louisiana State University Health Sciences Center in New Orleans
The University of Texas Health Science Center at Tyler
National Jewish Health
University of Kansas
University of North Carolina
James A. Haley Veterans Administration Hospital
Vancouver Clinic
Kaiser Permanente Hawaii

Investigators

  • Study Director: Emily Henkle, PhD, MPH, Oregon Health and Science University
  • Principal Investigator: Kevin L Winthrop, MD, MPH, Oregon Health and Science University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 22, 2019

Primary Completion (Estimated)

February 28, 2025

Study Completion (Estimated)

February 28, 2025

Study Registration Dates

First Submitted

September 11, 2018

First Submitted That Met QC Criteria

September 13, 2018

First Posted (Actual)

September 14, 2018

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

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 18819
  • PCS-2017C2-7764 (Other Grant/Funding Number: PCORI)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD 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)).

IPD Sharing Time Frame

The dataset will be available after completion of the study and publication of results.

IPD Sharing Access Criteria

Third party data requests will be reviewed by a committee, and approved requests will require a DUA.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP
  • ANALYTIC_CODE

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Mycobacterium Avium Complex

Clinical Trials on Azithromycin

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Tanzania

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

3
Subscribe