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.
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
474
Azithromycin 500 MG Oral Tablet \[ZITHROMAX\]
Ethambutol 25 mg/kg \[MYAMBUTOL\]
Rifampin 600 MG \[RIFADIN\]
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
...and 16 more locations
Acid-fast bacilli (AFB) culture negativity
Two consecutive negative AFB cultures by 12 months post randomization without reversion to positive
Time frame: 12 months post randomization
Therapy completion
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.
Time frame: 12 months post randomization
QOL-B Respiratory Symptoms Score
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.
Time frame: 12 months post randomization
NTM Symptoms Score
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.
Time frame: 12 months post randomization
PROMIS Fatigue 7a short form score
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.
Time frame: 12 months post randomization
Fatigue AE proportion
Self-report, Moderate or worse
Time frame: Cumulative to 12 months
Gastrointestinal AE proportion
Self-report, Moderate or worse: Nausea, diarrhea, decreased appetite, OR abdominal pain
Time frame: up to 12 months
Liver AE proportion
Laboratory grade 2 or higher abnormality
Time frame: up to 12 months
Macrolide resistance
Susceptibility at last positive culture
Time frame: 12 months post randomization
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