Comparison of Two- Versus Three-antibiotic Therapy for Pulmonary Mycobacterium Avium Complex Disease
MAC2v3
2 other identifiers
interventional
474
2 countries
26
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.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_2
Started Feb 2019
Longer than P75 for phase_2
26 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
September 11, 2018
CompletedFirst Posted
Study publicly available on registry
September 14, 2018
CompletedStudy Start
First participant enrolled
February 22, 2019
CompletedPrimary Completion
Last participant's last visit for primary outcome
January 8, 2026
CompletedStudy Completion
Last participant's last visit for all outcomes
January 8, 2026
CompletedFebruary 2, 2026
January 1, 2026
6.9 years
September 11, 2018
January 29, 2026
Conditions
Keywords
Outcome Measures
Primary Outcomes (2)
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 Outcomes (7)
QOL-B Respiratory Symptoms Score
12 months post randomization
NTM Symptoms Score
12 months post randomization
PROMIS Fatigue 7a short form score
12 months post randomization
Fatigue AE proportion
Cumulative to 12 months
Gastrointestinal AE proportion
up to 12 months
- +2 more secondary outcomes
Study Arms (2)
2-drug regimen
ACTIVE COMPARATORThis 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
ACTIVE COMPARATORThis 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.
Interventions
Azithromycin 500 MG Oral Tablet \[ZITHROMAX\]
Eligibility Criteria
You may qualify if:
- Culture positive pulmonary MAC meeting ATS/IDSA disease criteria
- Age over 18 years
- Ability to provide informed consent
You may not qualify if:
- 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
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- University of California, San Franciscocollaborator
- University Health Network, Torontocollaborator
- New York Universitycollaborator
- Medical University of South Carolinacollaborator
- Mayo Cliniccollaborator
- Louisiana State University Health Sciences Center in New Orleanscollaborator
- University of California, San Diegocollaborator
- Stanford Universitycollaborator
- University of Kansascollaborator
- Vancouver Cliniccollaborator
- University of Washingtoncollaborator
- Johns Hopkins Universitycollaborator
- University of Miamicollaborator
- Emory Universitycollaborator
- University of Iowacollaborator
- University of North Carolinacollaborator
- Temple Universitycollaborator
- Loma Linda Universitycollaborator
- Columbia Universitycollaborator
- University of Wisconsin, Madisoncollaborator
- Northwell Healthcollaborator
- Kaiser Permanentecollaborator
- James A. Haley Veterans Administration Hospitalcollaborator
- Kevin Winthroplead
- Patient-Centered Outcomes Research Institutecollaborator
- National Jewish Healthcollaborator
- The University of Texas Health Science Center at Tylercollaborator
Study Sites (26)
Loma Linda University Medical Center
Loma Linda, California, 92354, United States
University of California, San Diego
San Diego, California, 92103, United States
University of California, San Francisco
San Francisco, California, 94110, United States
Stanford University
Stanford, California, 94305, United States
National Jewish Health
Denver, Colorado, 80206, United States
University of Miami
Miami, Florida, 33136, United States
Tampa VA Medical Center
Tampa, Florida, 33612, United States
Emory University
Atlanta, Georgia, 30322, United States
Kaiser Permanente Hawaii
Honolulu, Hawaii, 96817, United States
University of Iowa
Iowa City, Iowa, 52242, United States
University of Kansas
Kansas City, Kansas, 66160, United States
Louisina State University
New Orleans, Louisiana, 70112, United States
Johns Hopkins University
Baltimore, Maryland, 21224, United States
Mayo Clinic
Rochester, Minnesota, 55905, United States
Northwell Health
Manhasset, New York, 11030, United States
New York University
New York, New York, 10016, United States
Columbia University Medical Center
New York, New York, 10032, United States
University of North Carolina
Chapel Hill, North Carolina, 27599, United States
Oregon Health & Science University
Portland, Oregon, 97239, United States
Temple University
Philadelphia, Pennsylvania, 19140, United States
Medical University of South Carolina
Charleston, South Carolina, 29425, United States
University of Texas Health Science Center
Tyler, Texas, 75708, United States
University of Washington
Seattle, Washington, 98104, United States
Vancouver Clinic
Vancouver, Washington, 98664, United States
University of Wisconsin School of Medicine and Public Health
Madison, Wisconsin, 53705, United States
University Health Network
Toronto, Ontario, M5T2S8, Canada
Related Publications (20)
Henkle E, Hedberg K, Schafer S, Novosad S, Winthrop KL. Population-based Incidence of Pulmonary Nontuberculous Mycobacterial Disease in Oregon 2007 to 2012. Ann Am Thorac Soc. 2015 May;12(5):642-7. doi: 10.1513/AnnalsATS.201412-559OC.
PMID: 25692495BACKGROUNDPrevots DR, Shaw PA, Strickland D, Jackson LA, Raebel MA, Blosky MA, Montes de Oca R, Shea YR, Seitz AE, Holland SM, Olivier KN. Nontuberculous mycobacterial lung disease prevalence at four integrated health care delivery systems. Am J Respir Crit Care Med. 2010 Oct 1;182(7):970-6. doi: 10.1164/rccm.201002-0310OC. Epub 2010 Jun 10.
PMID: 20538958BACKGROUNDWinthrop KL, McNelley E, Kendall B, Marshall-Olson A, Morris C, Cassidy M, Saulson A, Hedberg K. Pulmonary nontuberculous mycobacterial disease prevalence and clinical features: an emerging public health disease. Am J Respir Crit Care Med. 2010 Oct 1;182(7):977-82. doi: 10.1164/rccm.201003-0503OC. Epub 2010 May 27.
PMID: 20508209BACKGROUNDGriffith DE, Aksamit T, Brown-Elliott BA, Catanzaro A, Daley C, Gordin F, Holland SM, Horsburgh R, Huitt G, Iademarco MF, Iseman M, Olivier K, Ruoss S, von Reyn CF, Wallace RJ Jr, Winthrop K; ATS Mycobacterial Diseases Subcommittee; American Thoracic Society; Infectious Disease Society of America. An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007 Feb 15;175(4):367-416. doi: 10.1164/rccm.200604-571ST. No abstract available.
PMID: 17277290BACKGROUNDGriffith DE, Brown-Elliott BA, Shepherd S, McLarty J, Griffith L, Wallace RJ Jr. Ethambutol ocular toxicity in treatment regimens for Mycobacterium avium complex lung disease. Am J Respir Crit Care Med. 2005 Jul 15;172(2):250-3. doi: 10.1164/rccm.200407-863OC. Epub 2005 Apr 28.
PMID: 15860751BACKGROUNDLee H, Sohn YM, Ko JY, Lee SY, Jhun BW, Park HY, Jeon K, Kim DH, Kim SY, Choi JE, Moon IJ, Shin SJ, Park HJ, Koh WJ. Once-daily dosing of amikacin for treatment of Mycobacterium abscessus lung disease. Int J Tuberc Lung Dis. 2017 Jul 1;21(7):818-824. doi: 10.5588/ijtld.16.0791.
PMID: 28633708BACKGROUNDPeloquin CA, Berning SE, Nitta AT, Simone PM, Goble M, Huitt GA, Iseman MD, Cook JL, Curran-Everett D. Aminoglycoside toxicity: daily versus thrice-weekly dosing for treatment of mycobacterial diseases. Clin Infect Dis. 2004 Jun 1;38(11):1538-44. doi: 10.1086/420742. Epub 2004 May 5.
PMID: 15156439BACKGROUNDWinthrop KL, Ku JH, Marras TK, Griffith DE, Daley CL, Olivier KN, Aksamit TR, Varley CD, Mackey K, Prevots DR. The tolerability of linezolid in the treatment of nontuberculous mycobacterial disease. Eur Respir J. 2015 Apr;45(4):1177-9. doi: 10.1183/09031936.00169114. Epub 2015 Jan 22. No abstract available.
PMID: 25614169BACKGROUNDMiwa S, Shirai M, Toyoshima M, Shirai T, Yasuda K, Yokomura K, Yamada T, Masuda M, Inui N, Chida K, Suda T, Hayakawa H. Efficacy of clarithromycin and ethambutol for Mycobacterium avium complex pulmonary disease. A preliminary study. Ann Am Thorac Soc. 2014 Jan;11(1):23-9. doi: 10.1513/AnnalsATS.201308-266OC.
PMID: 24298907BACKGROUNDGriffith DE, Adjemian J, Brown-Elliott BA, Philley JV, Prevots DR, Gaston C, Olivier KN, Wallace RJ Jr. Semiquantitative Culture Analysis during Therapy for Mycobacterium avium Complex Lung Disease. Am J Respir Crit Care Med. 2015 Sep 15;192(6):754-60. doi: 10.1164/rccm.201503-0444OC.
PMID: 26068042BACKGROUNDKobashi Y, Matsushima T, Oka M. A double-blind randomized study of aminoglycoside infusion with combined therapy for pulmonary Mycobacterium avium complex disease. Respir Med. 2007 Jan;101(1):130-8. doi: 10.1016/j.rmed.2006.04.002. Epub 2006 Jun 5.
PMID: 16750618BACKGROUNDWallace RJ Jr, Brown-Elliott BA, McNulty S, Philley JV, Killingley J, Wilson RW, York DS, Shepherd S, Griffith DE. Macrolide/Azalide therapy for nodular/bronchiectatic mycobacterium avium complex lung disease. Chest. 2014 Aug;146(2):276-282. doi: 10.1378/chest.13-2538.
PMID: 24457542BACKGROUNDAdjemian J, Prevots DR, Gallagher J, Heap K, Gupta R, Griffith D. Lack of adherence to evidence-based treatment guidelines for nontuberculous mycobacterial lung disease. Ann Am Thorac Soc. 2014 Jan;11(1):9-16. doi: 10.1513/AnnalsATS.201304-085OC.
PMID: 24236749BACKGROUNDKoh WJ, Moon SM, Kim SY, Woo MA, Kim S, Jhun BW, Park HY, Jeon K, Huh HJ, Ki CS, Lee NY, Chung MJ, Lee KS, Shin SJ, Daley CL, Kim H, Kwon OJ. Outcomes of Mycobacterium avium complex lung disease based on clinical phenotype. Eur Respir J. 2017 Sep 27;50(3):1602503. doi: 10.1183/13993003.02503-2016. Print 2017 Sep.
PMID: 28954780BACKGROUNDHernan MA, Robins JM. Per-Protocol Analyses of Pragmatic Trials. N Engl J Med. 2017 Oct 5;377(14):1391-1398. doi: 10.1056/NEJMsm1605385. No abstract available.
PMID: 28976864BACKGROUNDMurray EJ, Hernan MA. Adherence adjustment in the Coronary Drug Project: A call for better per-protocol effect estimates in randomized trials. Clin Trials. 2016 Aug;13(4):372-8. doi: 10.1177/1740774516634335. Epub 2016 Mar 7.
PMID: 26951361BACKGROUNDWhite IR, Royston P, Wood AM. Multiple imputation using chained equations: Issues and guidance for practice. Stat Med. 2011 Feb 20;30(4):377-99. doi: 10.1002/sim.4067. Epub 2010 Nov 30.
PMID: 21225900BACKGROUNDU.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.
BACKGROUNDHenkle 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.
BACKGROUNDHenkle E, Quittner AL, Dieckmann NF, Franklin H, Brunton AE, Daley CL, Winthrop KL; MAC2v3 Investigators. Patient-Reported Symptom and Health-Related Quality-of-Life Validation and Responsiveness During the First 6 Months of Treatment for Mycobacterium avium Complex Pulmonary Disease. Chest. 2023 Jul;164(1):53-64. doi: 10.1016/j.chest.2023.02.015. Epub 2023 Feb 17.
PMID: 36803647DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- STUDY DIRECTOR
Emily Henkle, PhD, MPH
Oregon Health and Science University
- PRINCIPAL INVESTIGATOR
Kevin L Winthrop, MD, MPH
Oregon Health and Science University
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR INVESTIGATOR
- PI Title
- Professor
Study Record Dates
First Submitted
September 11, 2018
First Posted
September 14, 2018
Study Start
February 22, 2019
Primary Completion
January 8, 2026
Study Completion
January 8, 2026
Last Updated
February 2, 2026
Record last verified: 2026-01
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL, 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.
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)).