Impact of Discontinuing Dornase Alfa in People With CF on Highly Effective CFTR Modulator Therapy-A SIMPLIFY Sub-Study (SIMPLIFY-DN)

A Master Protocol to Test the Impact of Discontinuing Chronic Therapies in People With Cystic Fibrosis on Highly Effective CFTR Modulator Therapy - Dornase Alfa (Dnase)

Despite the increasingly common use of cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies in treating cystic fibrosis (CF), it is still largely unknown whether or not other chronic therapies can be safely stopped. This SIMPLIFY sub-study is being done to test whether or not it is safe to stop taking dornase alfa (Dnase) in those people that are also taking elexacaftor/tezacaftor/ivacaftor (ETI).

ETI is a combination CFTR modulator therapy that was approved by the Food and Drug Administration for people with CF who have at least one F508del mutation. The three drugs that make up ETI work together to allow many more chloride ions to move into and out of the cells, improving the balance of salt and water in the lungs. These changes result in better clearance of mucus from the lungs and improvements in lung function.

Dornase alfa (Dnase) also improves clearance of mucus from the lungs to support lung function and has been available to people with CF for many years. Dnase is considered to be relatively burdensome and it is not known whether Dnase can improve or maintain lung function above what is already gained through ETI use.

The goal of this SIMPLIFY sub-study is to get information about whether or not it is safe to stop Dnase by testing if there is a change in lung function in participants with cystic fibrosis (CF) who are assigned to stop taking Dnase as compared to those who are assigned to keep taking Dnase while continuing to take ETI.

This is a sub study of master protocol SIMPLIFY-IP-19, NCT04378153.

The sub study investigating the impact of discontinuing and continuing hypertonic saline is registered under NCTXXXXXXX (will add once available).

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Other: Discontinuation of dornase alfa (Dnase); Other: Continuation of dornase alfa (Dnase)

Detailed Description

This SIMPLIFY sub-study (Dornase Alfa (Dnase) Trial) is designed to evaluate the effects of discontinuing Dnase in people with cystic fibrosis (CF) age 12 and older currently taking the highly effective modulator elexacaftor/tezacaftor/ivacaftor (ETI). This is an open label two-arm randomized non-inferiority trial consisting of a 2-week screening period, randomization to continue or discontinue dornase alfa, followed by a 6-week study period. Participants at trial entry will be randomized 1:1 to either continue or discontinue their Dnase therapy.

Clinical outcomes (forced expiratory volume in 1 second [FEV1], antibiotic use, pulmonary exacerbations, and patient reported outcomes), safety (adverse events) and patient reported outcomes to evaluate respiratory symptoms and the participant's perception of how stopping Dnase would impact their daily life will be evaluated in all subjects. Additionally, a subset of participants at selected study sites will participate in Multiple Breath Washout (MBW) to evaluate changes in lung clearance index (LCI).

• Study Type: Interventional
• Enrollment (Actual): 477
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
  • Alaska
    • Anchorage, Alaska, United States, 99508
      • Providence Alaska Medical Center
  • Arizona
    • Tucson, Arizona, United States, 85724
      • Tucson Cystic Fibrosis Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hospital
  • California
    • Long Beach, California, United States, 90806
      • Miller Children's and Women's Hospital Long Beach
    • Orange, California, United States, 92868
      • CHOC Children's Hospital
    • Palo Alto, California, United States, 94304
      • Stanford University Medical Center
    • San Diego, California, United States, 92123
      • Rady Children's Hospital and Health Center at the University of California San Diego
    • San Francisco, California, United States, 94143
      • University of California, San Francisco - Adult Center
    • San Francisco, California, United States, 94158
      • University of California, San Francisco - Peds Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital 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
    • Jacksonville, Florida, United States, 32207
      • Nemours Children's Clinic - Jacksonville
    • Orlando, Florida, United States, 32803
      • Central Florida Pulmonary Group
    • Orlando, Florida, United States, 32827
      • The Nemours Children's Clinic - Orlando
    • Pensacola, Florida, United States, 32514
      • Nemours Children's Clinic - Pensacola
    • Saint Petersburg, Florida, United States, 33701
      • All Children's Hospital
    • Tampa, Florida, United States, 33606
      • Tampa General Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30324
      • Emory University
  • Idaho
    • Boise, Idaho, United States, 83702
      • Saint Luke's Cystic Fibrosis Center of Idaho
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Peoria, Illinois, United States, 61637
      • OSF Saint Francis Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40506
      • University of Kentucky
    • Louisville, Kentucky, United States, 40202
      • University of Louisville
  • Louisiana
    • Metairie, Louisiana, United States, 70001
      • Tulane University
  • Maine
    • Portland, Maine, United States, 04102
      • Maine Medical Partners Pediatric Specialty Care
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • John Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan, Michigan Medicine
    • Detroit, Michigan, United States, 48201
      • Wayne State University Harper University Hospital
    • Grand Rapids, Michigan, United States, 49546
      • Corewell Health Helen DeVos
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospitals and Clinics of 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, 63110
      • Washington University School of Medicine
  • Montana
    • Billings, Montana, United States, 59101
      • Billings Clinic
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center
  • New Jersey
    • Eatontown, New Jersey, United States, 07724
      • Monmouth Medical Center
    • Morristown, New Jersey, United States, 07960
      • Morristown Medical Center
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers - Robert Wood Johnson Medical School
  • New York
    • New Hyde Park, New York, United States, 11042
      • Cohen Children's Medical Center of New York
    • New York, New York, United States, 10003
      • Beth Israel Medical Center
    • New York, New York, United States, 10032
      • Columbia University Cystic Fibrosis Program
    • New York, New York, United States, 10028
      • Lenox Hill Hospital Cystic Fibrosis Center
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center Strong Memorial
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University
    • Valhalla, New York, United States, 10595
      • New York Medical College at Westchester Medical Center
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27517
      • University of North Carolina at Chapel Hill
    • Winston-Salem, North Carolina, United States, 27157
      • Atrium Health Wake Forest Baptist
  • Ohio
    • Akron, Ohio, United States, 44308
      • Children's Hospital Medical Center of Akron
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
    • Cleveland, Ohio, United States, 44146
      • Rainbow Babies and Children's Hospital/University Hospitals Cleveland Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Cystic Fibrosis Program
    • Columbus, Ohio, United States, 43205
      • Nationwide 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, 19104
      • University of Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • University of Pittsburgh Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Austin, Texas, United States, 78723
      • Dell Children's Medical Center of Central Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern
    • Dallas, Texas, United States, 75207
      • University of Texas Southwestern / Children's Health
    • Fort Worth, Texas, United States, 76104
      • Cook Children's Medical Center
    • Tyler, Texas, United States, 75708
      • University of Texas Health Center at Tyler
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Cystic Fibrosis Center
  • Vermont
    • Burlington, Vermont, United States, 05401
      • University of Vermont Medical Center
  • Virginia
    • Charlottesville, Virginia, United States, 22904
      • University of Virginia
    • Richmond, Virginia, United States, 23219
      • Virginia Commonwealth University
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center
    • Seattle, Washington, United States, 98105
      • Seattle Children's Hospital
    • Spokane, Washington, United States, 99204
      • Providence Medical Group, Cystic Fibrosis Center
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University - Morgantown
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert & Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of CF.
• Age ≥ 12 years at the Screening Visit.
• Forced expiratory volume in 1 second (FEV1) ≥ 70 % predicted at the Screening Visit if < 18 years old, and ≥ 60 % predicted at Screening Visit if ≥ 18 years old.
• Clinically stable with no significant changes in health status within the 7 days prior to and including the Screening Visit.
• Current treatment with elexacaftor/tezacaftor/ivacaftor (ETI) for at least the 90 days prior to and including the Screening Visit and willing to continue daily use for the duration of the study.
• Currently taking dornase alfa for at least the 90 days prior to and including the Screening Visit and willing to continue daily use for the 2-week screening period.

Exclusion Criteria:

• Active smoking or vaping.
• Use of an investigational drug within 28 days prior to and including the Screening Visit.
• Changes to chronic therapy (e.g., ibuprofen, azithromycin, inhaled tobramycin, aztreonam lysine) within 28 days prior to and including the Screening Visit. This includes new airway clearance routines.
• Acute use of antibiotics (oral, inhaled or IV) or acute use of systemic corticosteroids for respiratory tract symptoms within 7 days prior to and including the Screening Visit.
• Chronic use of systemic corticosteroids at a dose equivalent to ≥ 10mg per day of prednisone within 28 days prior to and including the Screening Visit.
• Antibiotic treatment for nontuberculous mycobacteria (NTM) within 28 days prior to and including the Screening Visit.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dnase - Discontinue; Discontinuation of current dornase alfa (dnase) therapy	Other: Discontinuation of dornase alfa (Dnase); Discontinuation of current dornase alfa (Dnase) therapy during 6-week study period.
Active Comparator: Dnase - Continue; Continuation of current dornase alfa (dnase) therapy	Other: Continuation of dornase alfa (Dnase); Continuation of current dornase alfa (dnase) therapy during 6-week study period. Therapy is taken at least once daily according to each participant's pre-existing, clinically prescribed regimen (e.g., daily, twice daily)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change in FEV1 % Predicted From Week 0 to Week 6	Difference between study arms (discontinue - continue) in the absolute change in FEV1 % predicted from Week 0 to Week 6.	Week 0 to Week 6

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Change in LCI 2.5 From Baseline to Week 6	Difference between study arms (discontinue - continue) in the absolute change in LCI 2.5 (Lung Clearance Index) from Baseline (Week 0, if available, or else Week -2) to Week 6. LCI 2.5 is the number of times the volume in the lungs needs to turn over to expel an inert gas. A higher value of LCI 2.5 indicates poorer lung function.	Baseline (Week 0 or Week -2) to Week 6
Absolute Change in Respiratory Symptoms, as Measured by the CF Respiratory Symptoms Diary-Chronic Respiratory Infection Symptom Severity Score (CRISS) From Week 0 to Week 6	Difference between study arms (discontinue - continue) in the absolute change in respiratory symptoms, as measured by the CF Respiratory Symptoms Diary-Chronic Respiratory Infection Symptom Severity Score (CRISS) from Week 0 to Week 6. The Cystic Fibrosis Respiratory Symptoms Daily Diary (CFRSD) asks a participant to state the extent of their 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 (range from 0-24) is calculated for each participant and converted to a final score with a range of 0 to 100, where the lowest scores indicate improvement of symptoms. Calculation of a score requires responses for at least 7 out of 8 symptoms.	Week 0 to Week 6
Absolute Change in Respiratory Symptoms, as Measured by CFQ-R Respiratory Domain From Week 0 to Week 6	Difference between study arms (discontinue - continue) in the absolute change in respiratory symptoms, as measured by the Cystic Fibrosis Questionnaire-Revised Respiratory Domain Score from Week 0 to Week 6. The Cystic Fibrosis Questionnaire - Revised asks participants 6 questions related to respiratory symptoms which are each assigned a score 1-4. The Respiratory Domain Scaled Score is calculated as follows: 100*[{sum of responses}/{number of responses}-1]/3 only if number of responses ≥ 3; otherwise the score is set to missing. The scaled score ranges from 0 to 100 where higher scores indicate improvement of symptoms.	Week 0 to Week 6
Absolute Change in FEV1 % Predicted From Week -2 to Week 0	Difference between study arms (discontinue - continue) in the absolute change in FEV1 % predicted from Week -2 to Week 0.	Week -2 to Week 0
Absolute Change in FEV1 % Predicted From Week 0 to Week 2	Difference between study arms (discontinue - continue) in the absolute change in FEV1 % predicted from Week 0 to Week 2.	Week 0 to Week 2
Number and Percent of Participants Initiating Acute Antibiotics From Week 0 to Week 6	Difference between study arms (discontinue - continue) in the percent of subjects initiating acute oral, inhaled or intravenous antibiotics from Week 0 to Week 6. Includes antibiotics initiated for respiratory indications; excludes those taken as part of a chronic cycled regimen or for a UTI, skin infection, etc.	Week 0 to Week 6
Number and Percent of Participants Hospitalized From Week 0 to Week 6	Difference between study arms (discontinue - continue) in the percent of subjects hospitalized from Week 0 to Week 6.	Week 0 to Week 6
Number and percent of participants Experiencing Pulmonary Exacerbations from Week 0 to Week 6	Difference between study arms (discontinue - continue) in the percent of subjects experiencing a pulmonary exacerbation from Week 0 to Week 6. Pulmonary exacerbations defined using Fuchs criteria.	Week 0 to Week 6
Number and Percent of Participants Experiencing Adverse Events (AEs) From Week 0 to Week 6	Difference between study arms (discontinue - continue) in the percent of participants with at least one AE from Week 0 to Week 6. Includes serious and non-serious AEs.	Week 0 to Week 6
Rate of Adverse Events (AEs) From Week 0 to Week 6 Therapy Arms	Comparison of study arms (discontinue/continue) in the rate of AE occurrence (number of events divided by total follow-up weeks in each arm) from Week 0 to Week 6. Includes serious and non-serious AEs.	Week 0 to Week 6
Number and Percent of Participants with Temporary or Permanent Changes From Assigned Therapy Regimen Due to Adverse Event From Week 0 to Week 6	Difference between study arms (discontinue - continue) in the percent of subjects temporarily or permanently changing their assigned therapy regimen due to an adverse event Week 0 to Week 6	Week 0 to Week 6

Collaborators and Investigators

• Sponsor: Nicole Hamblett
• Collaborators: University of Washington; Dartmouth-Hitchcock Medical Center; Cystic Fibrosis Foundation
• Investigators: Principal Investigator: Nicole Mayer-Hamblett, PhD, University of Washington/Seattle Children's; Principal Investigator: Alex Gifford, MD, FCCP, Dartmouth-Hitchcock Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): August 25, 2020
• Primary Completion (Actual): July 11, 2022
• Study Completion (Actual): July 11, 2022

Study Registration Dates

• First Submitted: April 1, 2024
• First Submitted That Met QC Criteria: April 1, 2024
• First Posted (Actual): April 5, 2024

Study Record Updates

• Last Update Posted (Actual): April 5, 2024
• Last Update Submitted That Met QC Criteria: April 1, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Cystic Fibrosis; Withdrawal; CF; discontinue; ETI; dornase alfa
• 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
• Other Study ID Numbers: SIMPLIFY-IP-19 Dnase

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No