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Mycobacterium Avium ComplexPhase 2/3MAC2v3NCT03672630

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

A Phase 2/3 study testing Azithromycin, Ethambutol and Rifampin in people with Mycobacterium Avium Complex and Nontuberculous Mycobacterium Infection, run by Kevin Winthrop at 26 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Azithromycin, Ethambutol and Rifampin
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
474 participants
Where
26 sitesin 2 countries
Study dates
22 Feb 2019to 8 Jan 2026
Phase
Phase 2/3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Culture positive pulmonary MAC meeting ATS/IDSA disease criteria
  • Age over 18 years
  • Ability to provide informed consent

Who cannot join

  • 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
Show all 9Show fewer
  • 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

Trial locations and contacts

26 sites in 2 countries.

26 sites in 2 countries

United States25 sites
  • Emory University

    Atlanta, Georgia, 30322

  • Johns Hopkins University

    Baltimore, Maryland, 21224

  • University of North Carolina

    Chapel Hill, North Carolina, 27599

  • Medical University of South Carolina

    Charleston, South Carolina, 29425

  • National Jewish Health

    Denver, Colorado, 80206

  • Kaiser Permanente Hawaii

    Honolulu, Hawaii, 96817

  • University of Iowa

    Iowa City, Iowa, 52242

  • University of Kansas

    Kansas City, Kansas, 66160

  • Loma Linda University Medical Center

    Loma Linda, California, 92354

  • University of Wisconsin School of Medicine and Public Health

    Madison, Wisconsin, 53705

  • Northwell Health

    Manhasset, New York, 11030

  • University of Miami

    Miami, Florida, 33136

  • Louisina State University

    New Orleans, Louisiana, 70112

  • New York University

    New York, New York, 10016

  • Columbia University Medical Center

    New York, New York, 10032

  • Temple University

    Philadelphia, Pennsylvania, 19140

  • Oregon Health & Science University

    Portland, Oregon, 97239

  • Mayo Clinic

    Rochester, Minnesota, 55905

  • University of California, San Diego

    San Diego, California, 92103

  • University of California, San Francisco

    San Francisco, California, 94110

  • University of Washington

    Seattle, Washington, 98104

  • Stanford University

    Stanford, California, 94305

  • Tampa VA Medical Center

    Tampa, Florida, 33612

  • University of Texas Health Science Center

    Tyler, Texas, 75708

  • Vancouver Clinic

    Vancouver, Washington, 98664

Other trials in United States

Canada1 site
  • University Health Network

    Toronto, Ontario, M5T2S8

Other trials in Canada

About this study

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.

Read the 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.

Being tested
Azithromycin, Ethambutol, Rifampin
Keywords
NTM, MAC, mycobacteria, nontuberculous mycobacteria, azithromycin, ethambutol, rifampin
Medical subject headings
Mycobacterium avium-intracellulare Infection, Mycobacterium Infections, Nontuberculous, Mycobacterium Infections

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • AzithromycinDrug

    Also called Zithromax

    Azithromycin 500 MG Oral Tablet [ZITHROMAX]

  • EthambutolDrug

    Also called Myambutol

    Ethambutol 25 mg/kg [MYAMBUTOL]

  • RifampinDrug

    Also called Rifadin

    Rifampin 600 MG [RIFADIN]

Study groups in NCT03672630
Study groupRoleWhat they receive
2-drug regimenActive 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.
Receives: Drug: Azithromycin; Drug: Ethambutol
3-drug regimenActive 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.
Receives: Drug: Azithromycin; Drug: Ethambutol; Drug: Rifampin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Acid-fast bacilli (AFB) culture negativity

    Two consecutive negative AFB cultures by 12 months post randomization without reversion to positive

    Measured: 12 months post randomization

  2. 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.

    Measured: 12 months post randomization

Secondary outcomes (7)
  1. 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.

    Measured: 12 months post randomization

  2. 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.

    Measured: 12 months post randomization

  3. 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.

    Measured: 12 months post randomization

  4. Fatigue AE proportion

    Self-report, Moderate or worse

    Measured: Cumulative to 12 months

  5. Gastrointestinal AE proportion

    Self-report, Moderate or worse: Nausea, diarrhea, decreased appetite, OR abdominal pain

    Measured: up to 12 months

  6. Liver AE proportion

    Laboratory grade 2 or higher abnormality

    Measured: up to 12 months

  7. Macrolide resistance

    Susceptibility at last positive culture

    Measured: 12 months post randomization

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted14 Sep 2018
  2. Study start22 Feb 2019
  3. Primary completion8 Jan 2026
  4. Study completion8 Jan 2026

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2/3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
474 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03672630
Sponsor's protocol ID
18819
Other IDs
PCS-2017C2-7764
Acronym
MAC2v3
Status last verified
Jan 2026
First submitted
11 Sep 2018
Last updated
2 Feb 2026
Results posted
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: 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)).

Publications

  • 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.

    PubMed 25692495
  • Prevots 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.

    PubMed 20538958
  • Winthrop 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.

    PubMed 20508209
  • Griffith 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.

    PubMed 17277290
  • Griffith 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.

    PubMed 15860751
  • Lee 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.

    PubMed 28633708
  • Peloquin 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.

    PubMed 15156439
  • Winthrop 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.

    PubMed 25614169
  • Miwa 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.

    PubMed 24298907
  • Griffith 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.

    PubMed 26068042
  • Kobashi 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.

    PubMed 16750618
  • Wallace 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.

    PubMed 24457542
  • Adjemian 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.

    PubMed 24236749
  • Koh 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.

    PubMed 28954780
  • Hernan 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.

    PubMed 28976864

Questions about this trial

What is this clinical trial studying?

A Phase 2/3 study testing Azithromycin, Ethambutol and Rifampin in people with Mycobacterium Avium Complex and Nontuberculous Mycobacterium Infection, run by Kevin Winthrop at 26 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 2 Feb 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 26 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Acid-fast bacilli (AFB) culture negativity (time frame: 12 months post randomization). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03672630, which also lists 20 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Feb 2026.

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