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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03672630
Recruitment Status : Recruiting
First Posted : September 14, 2018
Last Update Posted : October 13, 2021
Sponsor:
Collaborators:
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
Information provided by (Responsible Party):
Kevin Winthrop, Oregon Health and Science University

Study Description
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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
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Study Type : Interventional  (Clinical Trial)
Estimated 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 : February 22, 2019
Estimated Primary Completion Date : February 28, 2023
Estimated Study Completion Date : February 28, 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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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 Name: Zithromax

Drug: Ethambutol
Ethambutol 25 mg/kg [MYAMBUTOL]
Other Name: 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 Name: Zithromax

Drug: Ethambutol
Ethambutol 25 mg/kg [MYAMBUTOL]
Other Name: Myambutol

Drug: Rifampin
Rifampin 600 MG [RIFADIN]
Other Name: Rifadin


Outcome Measures
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Primary Outcome Measures :
  1. Acid-fast bacilli (AFB) culture negativity [ Time Frame: 12 months post randomization ]
    Two consecutive negative AFB cultures by 12 months post randomization without reversion to positive

  2. Therapy completion [ Time Frame: 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 :
  1. QOL-B Respiratory Symptoms Score [ Time Frame: 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.

  2. NTM Symptoms Score [ Time Frame: 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.

  3. PROMIS Fatigue 7a short form score [ Time Frame: 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.

  4. Fatigue AE proportion [ Time Frame: Cumulative to 12 months ]
    Self-report, Moderate or worse

  5. Gastrointestinal AE proportion [ Time Frame: up to 12 months ]
    Self-report, Moderate or worse: Nausea, diarrhea, decreased appetite, OR abdominal pain

  6. Liver AE proportion [ Time Frame: up to 12 months ]
    Laboratory grade 2 or higher abnormality

  7. Macrolide resistance [ Time Frame: 12 months post randomization ]
    Susceptibility at last positive culture


Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03672630


Contacts
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Contact: Haley Miller 503-346-1548 millehal@ohsu.edu
Contact: Daniel Bouchat 503-346-1548 johdanie@ohsu.edu

Locations
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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
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Study Director: Emily Henkle, PhD, MPH Oregon Health and Science University
Principal Investigator: Kevin L Winthrop, MD, MPH Oregon Health and Science University
More Information
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Publications:
U.S. Food and Drug Administration. FDA Guideline: Evaluation of Gender Differences in Clinical Investigations - Information Sheet, July 22, 1993. Found at https://www.fda.gov/RegulatoryInformation/Guidances/ucm126552.htm. Last accessed 6/11/18.
Henkle E, Novosad S, Siegel SA, Varley CD, Stadnik A, Winthrop KL. Northwest Biorepository of Nontuberculous Mycobacteria Patients- Baseline Characteristics. B25 NON-TUBERCULOUS MYCOBACTERIA: EPIDEMIOLOGY, DIAGNOSIS, AND TREATMENT: American Thoracic Society; 2016. p. A3018-A.

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Responsible Party: Kevin Winthrop, Professor, Oregon Health and Science University
ClinicalTrials.gov Identifier: NCT03672630    
Other Study ID Numbers: 18819
PCS-2017C2-7764 ( Other Grant/Funding Number: PCORI )
First Posted: September 14, 2018    Key Record Dates
Last Update Posted: October 13, 2021
Last Verified: October 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: A Full Data Package will be made available in a PCORI-designated repository. The Full Data Package includes the Analyzable Data Set, Full Protocol, metadata, data dictionary, full statistical analysis plan (including all amendments and all documentation for additional work processes), and analytic code from the PCORI-funded research project. The Analyzable Dataset includes a final cleaned and locked data set that contains all the data used in conducting the analyses reported in the PCORI Final Research Report and is de-identified in accordance with the HIPAA Privacy Rule (45 C.F.R. § 164.514(b)).
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Analytic Code
Time Frame: The dataset will be available after completion of the study and publication of results.
Access Criteria: Third party data requests will be reviewed by a committee, and approved requests will require a DUA.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Kevin Winthrop, Oregon Health and Science University:
NTM
MAC
mycobacteria
nontuberculous mycobacteria
 azithromycin
ethambutol
rifampin
Additional relevant MeSH terms:
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Mycobacterium Infections
Mycobacterium avium-intracellulare Infection
Mycobacterium Infections, Nontuberculous
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Bacterial Infections and Mycoses
Infections
Azithromycin
Rifampin
Ethambutol
Anti-Bacterial Agents
Anti-Infective Agents
 Antibiotics, Antitubercular
Antitubercular Agents
Leprostatic Agents
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cytochrome P-450 CYP2B6 Inducers
Cytochrome P-450 Enzyme Inducers
Cytochrome P-450 CYP2C8 Inducers
Cytochrome P-450 CYP2C19 Inducers
Cytochrome P-450 CYP2C9 Inducers
Cytochrome P-450 CYP3A Inducers