Testing the Effect of Adding Chronic Oral Azithromycin to Inhaled Tobramycin in People With Cystic Fibrosis (CF) (TEACH)

TEACH Trial: Testing the Effect of Adding CHronic Azithromycin to Inhaled Tobramycin. A Randomized, Placebo-controlled, Double-blinded Trial of Azithromycin 500mg Thrice Weekly in Combination With Inhaled Tobramycin

This is a study to examine the effect of combining chronic oral azithromycin with inhaled tobramycin in adolescent and adult subjects with cystic fibrosis who are chronically infected with P. aeruginosa.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: azithromycin; Drug: inhaled tobramycin; Drug: placebo (for azithromycin)

Detailed Description

This study is a prospective, randomized, double-blinded, placebo-controlled trial of azithromycin 500mg taken orally thrice weekly vs. placebo in subjects with cystic fibrosis and chronic airway infection with P. aeruginosa who are utilizing chronic inhaled tobramycin therapy. It will include approximately 120 subjects able to complete a primary 6-week study phase. Subjects will be at least 12 years old with a baseline forced expiratory volume at one second (FEV1) between 25-100% predicted. Subjects will continue to use clinically prescribed inhaled tobramycin cycled on/off every 4 weeks. They will be provided over-encapsulated azithromycin 500mg tablets or placebo during the primary study phase. An optional extension phase will be offered to all subjects completing the primary 6-week study. This 8-week extension phase will include an initial 4 weeks without use of inhaled tobramycin or other inhaled antibiotics, followed by a 4-week period with inhaled tobramycin use. All subjects participating in the extension phase of the study will be provided azithromycin 500mg tablets to be taken thrice weekly for the entire 8-week period.

This study will investigate how use of chronic oral azithromycin affects some of the previously demonstrated benefits to health when using inhaled tobramycin. The primary measurements will focus on lung function. Additional measurements will focus on disease-related quality of life as reported by subjects in the trial. Exploratory outcomes, including measurements of safety, are also planned.

• Study Type: Interventional
• Enrollment (Actual): 119
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hospital of Los Angeles
    • Palo Alto, California, United States, 94025
      • Stanford University Medical Center
    • San Diego, California, United States, 92123
      • Rady Children's Hospital and Health Center at the University of California San Diego
  • Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Health
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University School of Medicine
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
    • Orlando, Florida, United States, 32806
      • The Nemours Children's Clinic - Orlando
    • Pensacola, Florida, United States, 32504
      • Nemours Children's Clinic - Pensacola
  • Idaho
    • Boise, Idaho, United States, 83712
      • Saint Luke's Cystic Fibrosis Center of Idaho
  • Illinois
    • Chicago, Illinois, United States, 60208
      • Northwestern University
    • Peoria, Illinois, United States, 61637
      • Saint Francis Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Maine
    • Portland, Maine, United States, 04102
      • Maine Medical Partners Pediatric Specialty Care
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Memorial Health Care
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
    • Grand Rapids, Michigan, United States, 49503
      • Helen DeVos Children's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • The Minnesota Cystic Fibrosis Center
  • Missouri
    • Kansas City, Missouri, United States, 64108
      • Children's Mercy Kansas City
    • Saint Louis, Missouri, United States, 63104
      • Cardinal Glennon Children's Medical Center
    • Saint Louis, Missouri, United States, 63110
      • St. Louis Children's Hospital
  • New Jersey
    • Long Branch, New Jersey, United States, 07740
      • Monmouth Medical Center
  • New York
    • New York, New York, United States, 10003
      • Beth Israel Medical Center
    • New York, New York, United States, 10032
      • Children's Hospital of New York
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center Strong Memorial
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina At Chapel Hill
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center/Rainbow Babies and Children's Hospital
    • Dayton, Ohio, United States, 45404
      • Dayton Children's Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health Sciences University
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Hershey Medical Center Pennsylvania State University
    • Philadelphia, Pennsylvania, United States, 19134
      • St. Christopher's Hospital for Children
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Intermountain Cystic Fibrosis Center
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center
    • Seattle, Washington, United States, 98145
      • Seattle Children's Hospital
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 12 years old or older
• documented diagnosis of cystic fibrosis
• written informed consent (and assent when applicable)
• at least two respiratory cultures growing P. aeruginosa within the last 12 months
• FEV1% predicted between 25-100%
• use of at least two cycles of inhaled tobramycin within the last 24 weeks
• Off TISP and other inhaled anti-pseudomonal antibiotics for at least 2 weeks at Visit 1 and remain off of any inhaled antibiotics for an additional 2 weeks before starting inhaled tobramycin
• most recent liver function test results less than 4 times the upper limit of normal, obtained within the last 12 months
• prior or current use of azithromycin for at least four consecutive weeks
• stable clinical status and therapeutic regimen

Exclusion Criteria:

• weight <40 kg
• positive pregnancy test, lactating, or unwillingness to practice a pre-defined form of contraception, which includes abstinence
• inability to perform reproducible spirometry
• inability or unwillingness to cycle off of inhaled tobramycin for one 4-week period and without use of any additional inhaled antibiotics
• respiratory culture with Burkholderia cepacia complex species within 24 months or with nontuberculous mycobacteria within 18 months of screening
• use of intravenous or oral anti-pseudomonal antibiotics within 4 weeks of screening
• use of investigational therapy within 4 weeks of screening
• use of systemic corticosteroids equivalent to a daily dose more than 10mg of prednisone
• use of nelfinavir, warfarin, haloperidol, or methadone (concern of drug interaction with azithromycin)
• initiation of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy within 30 days
• ECG abnormality at screening requiring prompt further medical attention, or QTc interval >480 msec for males and >486 msec for females
• any other condition that, in the opinion of the site investigator, would compromise the safety of the subject or quality of the data

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: azithromycin; azithromycin 500mg tablet over-encapsulated to match placebo in appearance, taken by mouth thrice weekly for 6 weeks	Drug: azithromycin; 500mg tablet over-encapsulated to match placebo; Other Names: Zithromax; Drug: inhaled tobramycin; clinically prescribed inhaled tobramycin used by subjects participating in the study
Placebo Comparator: placebo; encapsulated placebo taken by mouth thrice weekly for 6 weeks	Drug: inhaled tobramycin; clinically prescribed inhaled tobramycin used by subjects participating in the study; Drug: placebo (for azithromycin)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative Change in Lung Function	Relative change in FEV1 volume (L) from enrollment at week 0 to the end of the 4-week period with inhaled tobramycin at week 6	baseline (week 0) to week 6 (6 week period)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relative Change in Lung Function	Relative change in FEV1 (L) from the beginning of the 4-week period with inhaled tobramycin at week 2 to the end of the 4-week period with inhaled tobramycin at week 6	week 2 to week 6 (4 week period)
Change in Cystic Fibrosis Respiratory Symptom Diary - Chronic Respiratory Infection Symptom Score (CFRSD-CRISS)	Absolute change in CFRSD-CRISS from enrollment at week 0 to the end of the 4-week period with inhaled tobramycin at week 6. The Cystic Fibrosis Respiratory Symptoms Diary asks a participant to state the extent of 8 respiratory symptoms: difficulty breathing, feverishness, tiredness, chills or sweats, coughing, coughing up mucus, tightness in the chest, and wheezing. Each respiratory symptom is assigned a score from 0-4 based on the response, with zero corresponding to the absence of the symptom and four corresponding to symptom being present "a great deal" or "extremely." A summed score (ranging from 0-24) is calculated for each participant and converted to a final score with a range of 0 to 100, where lower scores indicate improvement of symptoms.	baseline (week 0) to week 6 (6 week period)
Change in Cystic Fibrosis Questionnaire - Revised Respiratory Symptom Score (CFQ-R RSS)	Absolute change in the CFQ-R RSS from enrollment at week 0 to the end of the 4-week period with inhaled tobramycin at week 6. Age appropriate versions of Cystic Fibrosis Questionnaire - Revised ask a participant from 4 to 6 questions related to respiratory symptoms. The Respiratory Domain Scaled Score is calculated as follows: 100*[sum of {responses-1}] / [{number of responses}*3] only if [number of responses] ≥ [number of possible responses]/2; otherwise the score is set to missing. The scaled score ranges from 0 to 100 and higher scores indicate improvement of symptoms.	baseline (week 0) to week 6 (6 week period)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Sputum Pseudomonas Aeruginosa Bacterial Density	Absolute change in log10 transformed quantitative Pseudomonas aeruginosa (Pa) bacterial density as measured by colony forming units (CFUs) per mL of sputum from enrollment at week 0 to the end of the 4-week period with inhaled tobramycin at week 6. Culture results below the lower limit of detection of 1x10^2 were set to 1/2 of that LLD prior to log transformation.	baseline (week 0) to week 6 (6 week period)

Collaborators and Investigators

• Sponsor: Seattle Children's Hospital
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Cystic Fibrosis Foundation; CF Therapeutics Development Network Coordinating Center
• Investigators: Principal Investigator: David P Nichols, MD, National Jewish Health

Study record dates

Study Major Dates

• Study Start (Actual): October 21, 2016
• Primary Completion (Actual): February 13, 2020
• Study Completion (Actual): February 13, 2020

Study Registration Dates

• First Submitted: January 29, 2016
• First Submitted That Met QC Criteria: February 4, 2016
• First Posted (Estimate): February 9, 2016

Study Record Updates

• Last Update Posted (Actual): June 28, 2021
• Last Update Submitted That Met QC Criteria: June 3, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin; Tobramycin
• Other Study ID Numbers: TEACH-IP-15; 1R01HL124053-01A1 (U.S. NIH Grant/Contract); NICHOL15A0 (Other Grant/Funding Number: Cystic Fibrosis Foundation Therapeutics)