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

Mycobacterium Avium Complex Clinical Trial

— MAC2v3  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03672630
• Other study ID #: 18819
• Secondary ID: PCS-2017C2-7764
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: February 22, 2019
• Est. completion date: February 28, 2025

Study information

• Verified date: March 2024
• Source: Oregon Health and Science University
• Contact: Naomi DeBacker
• Phone: 503-346-3435
• Email: debacken[@]ohsu.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical 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. 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 500
• Est. completion date: February 28, 2025
• Est. primary completion date: February 28, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Mycobacterium Avium Complex
• Mycobacterium avium-intracellulare Infection
• Mycobacterium Infections
• Mycobacterium Infections, Nontuberculous
• Nontuberculous Mycobacterium Infection

Intervention

Drug:
• Azithromycin
Azithromycin 500 MG Oral Tablet [ZITHROMAX]
• Ethambutol
Ethambutol 25 mg/kg [MYAMBUTOL]
• Rifampin
Rifampin 600 MG [RIFADIN]

Locations

Country	Name	City	State
Canada	University Health Network	Toronto	Ontario
United States	Emory University	Atlanta	Georgia
United States	Johns Hopkins University	Baltimore	Maryland
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	National Jewish Health	Denver	Colorado
United States	Kaiser Permanente Hawaii	Honolulu	Hawaii
United States	University of Iowa	Iowa City	Iowa
United States	University of Kansas	Kansas City	Kansas
United States	Loma Linda University Medical Center	Loma Linda	California
United States	University of Wisconsin School of Medicine and Public Health	Madison	Wisconsin
United States	Northwell Health	Manhasset	New York
United States	University of Miami	Miami	Florida
United States	Yale University	New Haven	Connecticut
United States	Louisina State University	New Orleans	Louisiana
United States	Columbia University Medical Center	New York	New York
United States	New York University	New York	New York
United States	Temple University	Philadelphia	Pennsylvania
United States	Oregon Health & Science University	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	University of California, San Diego	San Diego	California
United States	University of California, San Francisco	San Francisco	California
United States	University of Washington	Seattle	Washington
United States	Stanford University	Stanford	California
United States	Tampa VA Medical Center	Tampa	Florida
United States	University of Texas Health Science Center	Tyler	Texas
United States	Vancouver Clinic	Vancouver	Washington
United States	Georgetown University	Washington	District of Columbia

Sponsors (27)

Lead Sponsor

Collaborator

Kevin Winthrop

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

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (19)

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. — View Citation

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. — View Citation

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

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. — View Citation

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. — View Citation

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.

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Murray 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. — View Citation

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. — View Citation

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. — View Citation

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.

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. — View Citation

White 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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Acid-fast bacilli (AFB) culture negativity	Two consecutive negative AFB cultures by 12 months post randomization without reversion to positive	12 months post randomization
Primary	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	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.	12 months post randomization
Secondary	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.	12 months post randomization
Secondary	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.	12 months post randomization
Secondary	Fatigue AE proportion	Self-report, Moderate or worse	Cumulative to 12 months
Secondary	Gastrointestinal AE proportion	Self-report, Moderate or worse: Nausea, diarrhea, decreased appetite, OR abdominal pain	up to 12 months
Secondary	Liver AE proportion	Laboratory grade 2 or higher abnormality	up to 12 months
Secondary	Macrolide resistance	Susceptibility at last positive culture	12 months post randomization