Clinical trial NCT03672630: Comparison of Two- Versus Three-antibiotic Therapy for Pulmonary Mycobacterium Avium Complex Disease
Official title: Comparison of Two- Versus Three-antibiotic Therapy for Pulmonary Mycobacterium Avium Complex Disease
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
PHASE3
Conditions: Mycobacterium Avium Complex
Nontuberculous Mycobacterium Infection
Keywords: NTM
MAC
mycobacteria
nontuberculous mycobacteria
azithromycin
ethambutol
rifampin
Lead sponsor: Oregon Health and Science University
Sponsor class: OTHER
Collaborators: name: Patient-Centered Outcomes Research Institute
name: National Jewish Health
name: The University of Texas Health Science Center at Tyler
name: University Health Network, Toronto
name: New York University
name: Medical University of South Carolina
name: Mayo Clinic
name: Louisiana State University Health Sciences Center in New Orleans
name: University of California, San Diego
name: Stanford University
name: University of Kansas
name: Vancouver Clinic
name: University of California, San Francisco
name: University of Washington
name: Johns Hopkins University
name: University of Miami
name: Emory University
name: University of Iowa
name: University of North Carolina
name: Temple University
name: Loma Linda University
name: Columbia University
name: University of Wisconsin, Madison
name: Northwell Health
name: Kaiser Permanente
name: James A. Haley Veterans Administration Hospital
First posted: 2018-09-14
Enrollment: 474
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Acid-fast bacilli (AFB) culture negativity
timeFrame: 12 months post randomization
measure: Therapy completion
timeFrame: 12 months post randomization
Secondary outcomes:
measure: QOL-B Respiratory Symptoms Score
timeFrame: 12 months post randomization
measure: NTM Symptoms Score
timeFrame: 12 months post randomization
measure: PROMIS Fatigue 7a short form score
timeFrame: 12 months post randomization
measure: Fatigue AE proportion
timeFrame: Cumulative to 12 months
measure: Gastrointestinal AE proportion
timeFrame: up to 12 months
measure: Liver AE proportion
timeFrame: up to 12 months
measure: Macrolide resistance
timeFrame: 12 months post randomization
Other outcomes:
Locations:
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center
state: California
city: San Diego
country: United States
facility: University of California, San Diego
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Stanford
country: United States
facility: Stanford University
state: California
city: Denver
country: United States
facility: National Jewish Health
state: Colorado
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Tampa
country: United States
facility: Tampa VA Medical Center
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Honolulu
country: United States
facility: Kaiser Permanente Hawaii
state: Hawaii
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas
state: Kansas
city: New Orleans
country: United States
facility: Louisina State University
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Manhasset
country: United States
facility: Northwell Health
state: New York
city: New York
country: United States
facility: New York University
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Chapel Hill
country: United States
facility: University of North Carolina
state: North Carolina
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Philadelphia
country: United States
facility: Temple University
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Tyler
country: United States
facility: University of Texas Health Science Center
state: Texas
city: Seattle
country: United States
facility: University of Washington
state: Washington
city: Vancouver
country: United States
facility: Vancouver Clinic
state: Washington
city: Madison
country: United States
facility: University of Wisconsin School of Medicine and Public Health
state: Wisconsin
city: Toronto
country: Canada
facility: University Health Network
state: Ontario
Study officials:
affiliation: Oregon Health and Science University
name: Emily Henkle, PhD, MPH
role: STUDY_DIRECTOR
affiliation: Oregon Health and Science University
name: Kevin L Winthrop, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
citation: 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.
citation: 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.
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.
citation: 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.
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.
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.
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.
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.