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

NCT ID: NCT03672630

Last Updated: 2024-12-04

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 474 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-02-22
• Study Completion Date: 2025-10-25

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.

Conditions

Mycobacterium Avium Complex; Nontuberculous Mycobacterium Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Azithromycin

Intervention Type: DRUG

Azithromycin 500 MG Oral Tablet \[ZITHROMAX\]

Ethambutol

Intervention Type: DRUG

Ethambutol 25 mg/kg \[MYAMBUTOL\]

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.

Group Type: ACTIVE_COMPARATOR

Azithromycin

Intervention Type: DRUG

Azithromycin 500 MG Oral Tablet \[ZITHROMAX\]

Ethambutol

Intervention Type: DRUG

Ethambutol 25 mg/kg \[MYAMBUTOL\]

Rifampin

Intervention Type: DRUG

Rifampin 600 MG \[RIFADIN\]

Interventions

Azithromycin

Azithromycin 500 MG Oral Tablet \[ZITHROMAX\]

Intervention Type: DRUG

Ethambutol

Ethambutol 25 mg/kg \[MYAMBUTOL\]

Intervention Type: DRUG

Rifampin

Rifampin 600 MG \[RIFADIN\]

Intervention Type: DRUG

Other Intervention Names

Zithromax; Myambutol; Rifadin

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Patient-Centered Outcomes Research Institute

OTHER

Sponsor Role: collaborator

National Jewish Health

OTHER

Sponsor Role: collaborator

The University of Texas Health Science Center at Tyler

OTHER

Sponsor Role: collaborator

University Health Network, Toronto

OTHER

Sponsor Role: collaborator

New York University

OTHER

Sponsor Role: collaborator

Medical University of South Carolina

OTHER

Sponsor Role: collaborator

Mayo Clinic

OTHER

Sponsor Role: collaborator

Louisiana State University Health Sciences Center in New Orleans

OTHER

Sponsor Role: collaborator

University of California, San Diego

OTHER

Sponsor Role: collaborator

Stanford University

OTHER

Sponsor Role: collaborator

University of Kansas

OTHER

Sponsor Role: collaborator

Vancouver Clinic

UNKNOWN

Sponsor Role: collaborator

University of California, San Francisco

OTHER

Sponsor Role: collaborator

University of Washington

OTHER

Sponsor Role: collaborator

Johns Hopkins University

OTHER

Sponsor Role: collaborator

University of Miami

OTHER

Sponsor Role: collaborator

Emory University

OTHER

Sponsor Role: collaborator

University of Iowa

OTHER

Sponsor Role: collaborator

University of North Carolina

OTHER

Sponsor Role: collaborator

Temple University

OTHER

Sponsor Role: collaborator

Loma Linda University

OTHER

Sponsor Role: collaborator

Columbia University

OTHER

Sponsor Role: collaborator

University of Wisconsin, Madison

OTHER

Sponsor Role: collaborator

Northwell Health

OTHER

Sponsor Role: collaborator

Kaiser Permanente

OTHER

Sponsor Role: collaborator

James A. Haley Veterans Administration Hospital

FED

Sponsor Role: collaborator

Kevin Winthrop

OTHER

Sponsor Role: lead

Responsible Party

Kevin Winthrop

Professor

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Emily Henkle, PhD, MPH

Role: STUDY_DIRECTOR

Oregon Health and Science University

Kevin L Winthrop, MD, MPH

Role: PRINCIPAL_INVESTIGATOR

Oregon Health and Science University

Locations

Loma Linda University Medical Center

Loma Linda, California, United States

University of California, San Diego

San Diego, California, United States

University of California, San Francisco

San Francisco, California, United States

Stanford University

Stanford, California, United States

National Jewish Health

Denver, Colorado, United States

University of Miami

Miami, Florida, United States

Tampa VA Medical Center

Tampa, Florida, United States

Emory University

Atlanta, Georgia, United States

Kaiser Permanente Hawaii

Honolulu, Hawaii, United States

University of Iowa

Iowa City, Iowa, United States

University of Kansas

Kansas City, Kansas, United States

Louisina State University

New Orleans, Louisiana, United States

Johns Hopkins University

Baltimore, Maryland, United States

Mayo Clinic

Rochester, Minnesota, United States

Northwell Health

Manhasset, New York, United States

New York University

New York, New York, United States

Columbia University Medical Center

New York, New York, United States

University of North Carolina

Chapel Hill, North Carolina, United States

Oregon Health & Science University

Portland, Oregon, United States

Temple University

Philadelphia, Pennsylvania, United States

Medical University of South Carolina

Charleston, South Carolina, United States

University of Texas Health Science Center

Tyler, Texas, United States

University of Washington

Seattle, Washington, United States

Vancouver Clinic

Vancouver, Washington, United States

University of Wisconsin School of Medicine and Public Health

Madison, Wisconsin, United States

University Health Network

Toronto, Ontario, Canada

Countries

United States; Canada

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Other Identifiers

PCS-2017C2-7764

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

18819

Identifier Type: -

Identifier Source: org_study_id