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

Kevin Winthrop

Status and phase: Active, not recruiting; Phase 3; Phase 2

Conditions: Mycobacterium Avium Complex; Nontuberculous Mycobacterium Infection

Treatments: Drug: Ethambutol; Drug: Azithromycin; Drug: Rifampin

Study type: Interventional

Funder types: Other; Other U.S. Federal agency

Identifiers

NCT03672630

18819

PCS-2017C2-7764 (Other Grant/Funding Number)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 474 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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474 participants in 2 patient groups

2-drug regimen

Active Comparator group

Description:

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.

Treatment:

Drug: Azithromycin

Drug: Ethambutol

3-drug regimen

Active Comparator group

Description:

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.

Treatment:

Drug: Rifampin

Drug: Azithromycin

Drug: Ethambutol