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

Sponsor

Kevin Winthrop (Other)

Overall Status

Recruiting

CT.gov ID

NCT03672630

Collaborator

Patient-Centered Outcomes Research Institute (Other), National Jewish Health (Other), The University of Texas Health Science Center at Tyler (Other), University Health Network, Toronto (Other), New York University (Other), Medical University of South Carolina (Other), Mayo Clinic (Other), Louisiana State University Health Sciences Center in New Orleans (Other), University of California, San Diego (Other), Stanford University (Other), University of Kansas (Other), Vancouver Clinic (Other), University of California, San Francisco (Other), University of Washington (Other), Johns Hopkins University (Other), University of Miami (Other), Emory University (Other), University of Iowa (Other), University of North Carolina (Other), Temple University (Other), Loma Linda University (Other), Columbia University (Other), University of Wisconsin, Madison (Other), Northwell Health (Other)

500

Enrollment

Locations

Arms

48.2

Anticipated Duration (Months)

18.5

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Mycobacterium Avium Complex Nontuberculous Mycobacterium Infection	Drug: Azithromycin Drug: Ethambutol Drug: Rifampin	Phase 2/Phase 3

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

500 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Feb 22, 2019

Anticipated Primary Completion Date :

Feb 28, 2023

Anticipated Study Completion Date :

Feb 28, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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.	Drug: Azithromycin Azithromycin 500 MG Oral Tablet [ZITHROMAX] Other Names: Zithromax Drug: Ethambutol Ethambutol 25 mg/kg [MYAMBUTOL] Other Names: Myambutol
Active Comparator: 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.	Drug: Azithromycin Azithromycin 500 MG Oral Tablet [ZITHROMAX] Other Names: Zithromax Drug: Ethambutol Ethambutol 25 mg/kg [MYAMBUTOL] Other Names: Myambutol Drug: Rifampin Rifampin 600 MG [RIFADIN] Other Names: Rifadin

Arm

Intervention/Treatment

Active Comparator: 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.

Drug: Azithromycin

Azithromycin 500 MG Oral Tablet [ZITHROMAX]

Other Names:

Zithromax

Drug: Ethambutol

Ethambutol 25 mg/kg [MYAMBUTOL]

Other Names:

Myambutol

Active Comparator: 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.

Drug: Azithromycin

Azithromycin 500 MG Oral Tablet [ZITHROMAX]

Other Names:

Zithromax

Drug: Ethambutol

Ethambutol 25 mg/kg [MYAMBUTOL]

Other Names:

Myambutol

Drug: Rifampin

Rifampin 600 MG [RIFADIN]

Other Names:

Rifadin

Outcome Measures

Primary Outcome Measures

Acid-fast bacilli (AFB) culture negativity [12 months post randomization]
Two consecutive negative AFB cultures by 12 months post randomization without reversion to positive
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.

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Loma Linda University Medical Center	Loma Linda	California	United States	92354
2	University of California, San Diego	San Diego	California	United States	92103
3	University of California, San Francisco	San Francisco	California	United States	94110
4	Stanford University	Stanford	California	United States	94305
5	National Jewish Health	Denver	Colorado	United States	80206
6	Yale University	New Haven	Connecticut	United States	06520
7	Georgetown University	Washington	District of Columbia	United States	20007
8	University of Miami	Miami	Florida	United States	33136
9	Emory University	Atlanta	Georgia	United States	30322
10	Kaiser Permanente Hawaii	Honolulu	Hawaii	United States	96817
11	University of Iowa	Iowa City	Iowa	United States	52242
12	University of Kansas	Kansas City	Kansas	United States	66160
13	Louisina State University	New Orleans	Louisiana	United States	70112
14	Johns Hopkins University	Baltimore	Maryland	United States	21224
15	Mayo Clinic	Rochester	Minnesota	United States	55905
16	Northwell Health	Manhasset	New York	United States	11030
17	New York University	New York	New York	United States	10016
18	Columbia University Medical Center	New York	New York	United States	10032
19	University of North Carolina	Chapel Hill	North Carolina	United States	27599
20	Oregon Health & Science University	Portland	Oregon	United States	97239
21	Temple University	Philadelphia	Pennsylvania	United States	19140
22	Medical University of South Carolina	Charleston	South Carolina	United States	29425
23	University of Texas Health Science Center	Tyler	Texas	United States	75708
24	University of Washington	Seattle	Washington	United States	98104
25	Vancouver Clinic	Vancouver	Washington	United States	98664
26	University of Wisconsin School of Medicine and Public Health	Madison	Wisconsin	United States	53705
27	University Health Network	Toronto	Ontario	Canada	M5T2S8

Sponsors and Collaborators

Kevin Winthrop
Patient-Centered Outcomes Research Institute
National Jewish Health
The University of Texas Health Science Center at Tyler
University Health Network, Toronto
New York University
Medical University of South Carolina
Mayo Clinic
Louisiana State University Health Sciences Center in New Orleans
University of California, San Diego
Stanford University
University of Kansas
Vancouver Clinic
University of California, San Francisco
University of Washington
Johns Hopkins University
University of Miami
Emory University
University of Iowa
University of North Carolina
Temple University
Loma Linda University
Columbia University
University of Wisconsin, Madison
Northwell Health

Investigators

Study Director: Emily Henkle, PhD, MPH, Oregon Health and Science University
Principal Investigator: Kevin L Winthrop, MD, MPH, Oregon Health and Science University