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

Cystic Fibrosis Clinical Trial

— SIMPLIFY-DN  

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT06350474
• Other study ID #: SIMPLIFY-IP-19 Dnase
• Status: Completed
• Phase: N/A
• Start date: August 25, 2020
• Est. completion date: July 11, 2022

Study information

• Verified date: April 2024
• Source: Seattle Children's Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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).

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 477
• Est. completion date: July 11, 2022
• Est. primary completion date: July 11, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis

Intervention

Other:
• Discontinuation of dornase alfa (Dnase)
Discontinuation of current dornase alfa (Dnase) therapy during 6-week study period.
• 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)

Locations

Country	Name	City	State
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	Providence Alaska Medical Center	Anchorage	Alaska
United States	University of Michigan, Michigan Medicine	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Dell Children's Medical Center of Central Texas	Austin	Texas
United States	John Hopkins Hospital	Baltimore	Maryland
United States	Billings Clinic	Billings	Montana
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Saint Luke's Cystic Fibrosis Center of Idaho	Boise	Idaho
United States	Boston Children's Hospital	Boston	Massachusetts
United States	University of Vermont Medical Center	Burlington	Vermont
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	University of Virginia	Charlottesville	Virginia
United States	Northwestern University	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Cystic Fibrosis Program	Cleveland	Ohio
United States	Rainbow Babies and Children's Hospital/University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	University of Texas Southwestern	Dallas	Texas
United States	University of Texas Southwestern / Children's Health	Dallas	Texas
United States	Dayton Children's Hospital	Dayton	Ohio
United States	National Jewish Health	Denver	Colorado
United States	Wayne State University Harper University Hospital	Detroit	Michigan
United States	Monmouth Medical Center	Eatontown	New Jersey
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	University of Florida	Gainesville	Florida
United States	Corewell Health Helen DeVos	Grand Rapids	Michigan
United States	Hershey Medical Center Pennsylvania State University	Hershey	Pennsylvania
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Iowa	Iowa City	Iowa
United States	Nemours Children's Clinic - Jacksonville	Jacksonville	Florida
United States	Children's Mercy Kansas City	Kansas City	Missouri
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	University of Kentucky	Lexington	Kentucky
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Miller Children's and Women's Hospital Long Beach	Long Beach	California
United States	University of Louisville	Louisville	Kentucky
United States	University of Wisconsin	Madison	Wisconsin
United States	Tulane University	Metairie	Louisiana
United States	Children's Wisconsin	Milwaukee	Wisconsin
United States	Froedtert & Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Children's Hospitals and Clinics of Minnesota	Minneapolis	Minnesota
United States	The Minnesota Cystic Fibrosis Center	Minneapolis	Minnesota
United States	West Virginia University - Morgantown	Morgantown	West Virginia
United States	Morristown Medical Center	Morristown	New Jersey
United States	Rutgers - Robert Wood Johnson Medical School	New Brunswick	New Jersey
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Cohen Children's Medical Center of New York	New Hyde Park	New York
United States	Beth Israel Medical Center	New York	New York
United States	Columbia University Cystic Fibrosis Program	New York	New York
United States	Lenox Hill Hospital Cystic Fibrosis Center	New York	New York
United States	CHOC Children's Hospital	Orange	California
United States	Central Florida Pulmonary Group	Orlando	Florida
United States	The Nemours Children's Clinic - Orlando	Orlando	Florida
United States	Stanford University Medical Center	Palo Alto	California
United States	Nemours Children's Clinic - Pensacola	Pensacola	Florida
United States	OSF Saint Francis Medical Center	Peoria	Illinois
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Maine Medical Partners Pediatric Specialty Care	Portland	Maine
United States	Oregon Health & Sciences University	Portland	Oregon
United States	Virginia Commonwealth University	Richmond	Virginia
United States	University of Rochester Medical Center Strong Memorial	Rochester	New York
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Cystic Fibrosis Center	Salt Lake City	Utah
United States	Rady Children's Hospital and Health Center at the University of California San Diego	San Diego	California
United States	University of California, San Francisco - Adult Center	San Francisco	California
United States	University of California, San Francisco - Peds Center	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	University of Washington Medical Center	Seattle	Washington
United States	Providence Medical Group, Cystic Fibrosis Center	Spokane	Washington
United States	SUNY Upstate Medical University	Syracuse	New York
United States	Tampa General Hospital	Tampa	Florida
United States	Tucson Cystic Fibrosis Center	Tucson	Arizona
United States	University of Texas Health Center at Tyler	Tyler	Texas
United States	New York Medical College at Westchester Medical Center	Valhalla	New York
United States	Atrium Health Wake Forest Baptist	Winston-Salem	North Carolina

Sponsors (4)

Lead Sponsor	Collaborator
Nicole Hamblett	Cystic Fibrosis Foundation, Dartmouth-Hitchcock Medical Center, University of Washington

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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