Comparison of Two- Versus Three-antibiotic Therapy for Pulmonary Mycobacterium Avium Complex Disease
- Conditions
- Nontuberculous Mycobacterium InfectionMycobacterium Avium Complex
- Interventions
- Registration Number
- NCT03672630
- Lead Sponsor
- Kevin Winthrop
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 474
- Culture positive pulmonary MAC meeting ATS/IDSA disease criteria
- Age over 18 years
- Ability to provide informed consent
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description 2-drug regimen Azithromycin 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. 2-drug regimen Ethambutol 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. 3-drug regimen Azithromycin 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. 3-drug regimen Ethambutol 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. 3-drug regimen Rifampin 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.
- Primary Outcome Measures
Name Time Method Therapy completion 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.
Acid-fast bacilli (AFB) culture negativity 12 months post randomization Two consecutive negative AFB cultures by 12 months post randomization without reversion to positive
- Secondary Outcome Measures
Name Time Method Gastrointestinal AE proportion up to 12 months Self-report, Moderate or worse: Nausea, diarrhea, decreased appetite, OR abdominal pain
Fatigue AE proportion Cumulative to 12 months Self-report, Moderate or worse
NTM Symptoms Score 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.
PROMIS Fatigue 7a short form score 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.
QOL-B Respiratory Symptoms Score 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.
Liver AE proportion up to 12 months Laboratory grade 2 or higher abnormality
Macrolide resistance 12 months post randomization Susceptibility at last positive culture
Trial Locations
- Locations (26)
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