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

• ClinicalTrials.gov Identifier: NCT03672630
• Recruitment Status: Recruiting
• First Posted: September 14, 2018
• Last Update Posted: December 4, 2019
• Sponsor: Kevin Winthrop
• 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; Georgetown University; University of Chicago; 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; Yale University; Temple University; Loma Linda University; Columbia University; University of Wisconsin, Madison
• Information provided by (Responsible Party): Kevin Winthrop, Oregon Health and Science University

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 (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

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 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

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

Eligibility Criteria

• 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
• Prior multi-drug therapy for pulmonary NTM
• Cystic fibrosis
• 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

Contacts

Contact: Andie Hendrick; 503-494-2136; hendrmic@ohsu.edu

Contact: Megan E Wardrop, MS; 503-346-3752; wardrop@ohsu.edu

  Show 26 Study Locations

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

Georgetown University

University of Chicago

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

Yale University

Temple University

Loma Linda University

Columbia University

University of Wisconsin, Madison

Investigators

• 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

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.

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.

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.

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. Review. Erratum in: Am J Respir Crit Care Med. 2007 Apr 1;175(7):744-5. Dosage error in article text.

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. Epub 2005 Apr 28.

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.

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. Epub 2004 May 5.

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.

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.

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.

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. Epub 2006 Jun 5.

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.

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.

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). pii: 1602503. doi: 10.1183/13993003.02503-2016. Print 2017 Sep.

Hernán MA, Robins JM. Per-Protocol Analyses of Pragmatic Trials. N Engl J Med. 2017 Oct 5;377(14):1391-1398. doi: 10.1056/NEJMsm1605385.

Murray EJ, Hernán 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.

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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.

• Responsible Party: Kevin Winthrop, Professor, Oregon Health and Science University
• ClinicalTrials.gov Identifier: NCT03672630 History of Changes
• Other Study ID Numbers: 18819; PCS-2017C2-7764 ( Other Grant/Funding Number: PCORI )
• First Posted: September 14, 2018
• Last Update Posted: December 4, 2019
• Last Verified: December 2019

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.

• 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:

Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antitubercular; Antitubercular Agents; Leprostatic Agents; Mycobacterium Infections; Mycobacterium avium-intracellulare Infection; Mycobacterium Infections, Nontuberculous; Actinomycetales Infections; Gram-Positive Bacterial Infections; Bacterial Infections; Rifampin; Ethambutol; Azithromycin; 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