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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Mycobacterium Avium Complex, Nontuberculous Mycobacterium Infection

Intervention / Treatment
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* Drug: Azithromycin
* Drug: Ethambutol
* Drug: Rifampin


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 2-drug regimen<br>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<br>* Azithromycin 500 MG Oral Tablet [ZITHROMAX]<br>* Other names: Zithromax;Drug: Ethambutol<br>* Ethambutol 25 mg/kg [MYAMBUTOL]<br>* Other names: Myambutol;|
| Active Comparator: 3-drug regimen<br>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<br>* Azithromycin 500 MG Oral Tablet [ZITHROMAX]<br>* Other names: Zithromax;Drug: Ethambutol<br>* Ethambutol 25 mg/kg [MYAMBUTOL]<br>* Other names: Myambutol;Drug: Rifampin<br>* Rifampin 600 MG [RIFADIN]<br>* Other names: Rifadin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acid-fast bacilli (AFB) culture negativity | Two consecutive negative AFB cultures by 12 months post randomization without reversion to positive | 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. | 12 months post randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 12 months post randomization | 
| Fatigue AE proportion | Self-report, Moderate or worse | Cumulative to 12 months | 
| Gastrointestinal AE proportion | Self-report, Moderate or worse: Nausea, diarrhea, decreased appetite, OR abdominal pain | up to 12 months | 
| Liver AE proportion | Laboratory grade 2 or higher abnormality | up to 12 months | 
| Macrolide resistance | Susceptibility at last positive culture | 12 months post randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NTM, MAC, mycobacteria, nontuberculous mycobacteria, azithromycin, ethambutol, rifampin