Impact of Discontinuing Chronic Therapies in People With Cystic Fibrosis on Highly Effective CFTR Modulator Therapy

Cystic Fibrosis Clinical Trial

— SIMPLIFY  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04378153
• Other study ID #: SIMPLIFY-IP-19
• Status: Completed
• Phase: N/A
• Start date: August 25, 2020
• Est. completion date: July 11, 2022

Study information

• Verified date: January 2023
• 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 CF, it is still largely unknown whether or not other chronic therapies can be safely stopped. The SIMPLIFY study is being done to test whether or not it is safe to stop taking inhaled hypertonic saline or Pulmozyme® (dornase alfa) in those people that are also taking Trikafta™.

Trikafta (elexacaftor/tezacaftor/ivacaftor) 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 Trikafta 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.

Inhaled hypertonic saline and Pulmozyme (dornase alfa) also improve clearance of mucus from the lungs to support lung function and have been available to people with CF for many years. Both therapies are considered to be relatively burdensome and it is not known whether either therapy can improve or maintain lung function above what is already gained through Trikafta use.

The goal of the SIMPLIFY study is to get information about whether or not it is safe to stop either inhaled hypertonic saline or Pulmozyme (dornase alfa) by testing if there is a change in lung function in subjects with cystic fibrosis (CF) who are assigned to stop their chronic medication (either hypertonic saline or Pulmozyme) as compared to those who are assigned to keep taking their medication while continuing to take Trikafta.

Description:

This master protocol is designed to evaluate the independent effects of discontinuing hypertonic saline (Study A) and dornase alfa (Study B) in people with cystic fibrosis (CF) age 12 and older currently taking the highly effective modulator elexacaftor/tezacaftor/ivacaftor (ETI). Study A and Study B are identical open label two-arm randomized non-inferiority trials consisting of a 2-week screening period, randomization to continue or discontinue hypertonic saline (Study A) or dornase alfa (Study B), followed by a 6-week study period. Subjects taking only hypertonic saline (HS) or dornase alfa at trial entry will be randomized 1:1 to either continue or discontinue the applicable therapy (i.e. HS or dornase alfa). Subjects taking both hypertonic saline and dornase alfa at study entry will be randomized to participate in either Study A or Study B and will be randomized (1:1) to continue or discontinue the applicable therapy (i.e. HS or dornase alfa). After completion of the first study, eligible subjects may subsequently enroll in the alternative study.

Clinical outcomes (forced expiratory volume in 1 second [FEV1], antibiotic use, pulmonary exacerbations, and patient reported outcomes), safety (adverse events) and the subject's perception of how stopping HS or dornase alfa (or both) would impact their daily life will be evaluated in all subjects. Additional outcome measurements will be conducted in a subset of subjects at selected study sites:

• Multiple Breath Washout (MBW) to evaluate changes in lung clearance index (LCI)

• Mucociliary Clearance (MCC) using inhaled radio-labeled particles to evaluate changes in mucociliary clearance

Recruitment information / eligibility

• Status: Completed
• Enrollment: 870
• 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 hypertonic saline (at least 3%) and/or 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 hypertonic saline (HS)
Discontinuation of current hypertonic saline (HS) therapy in Study A during 6-week study period.
• Continuation of hypertonic saline (HS)
Continuation of current hypertonic saline (HS) therapy in Study A 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). The concentration of HS is according to clinical prescription (e.g., 7% sodium chloride or 3.5% sodium chloride) and at least 3%.
• Discontinuation of dornase alfa (dnase)
Discontinuation of current dornase alfa (dnase) therapy in Study B during 6-week study period.
• Continuation of dornase alfa (dnase)
Continuation of current dornase alfa (dnase) therapy in Study B 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, Brigham & Women'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	Helen DeVos Children's Hospital	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	Florida
United States	Children's Mercy Kansas City	Kansas City	Missouri
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Cohen Children's Medical Center of New York	Lake Success	New York
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 Hospital of 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	Beth Israel Medical Center	New York	New York
United States	Columbia University Cystic Fibrosis Program	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	Wake Forest University Baptist Medical Center	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 in Hypertonic Saline (Study A) Therapy Arms	Difference between hypertonic saline (HS) therapy arms (HS-discontinue - HS-continue) in the absolute change in FEV1 % predicted from Week 0 to Week 6.	Week 0 to Week 6
Primary	Absolute change in FEV1 % predicted from Week 0 to Week 6 in Dornase Alfa (Study B) Therapy Arms	Difference between dornase alfa (dnase) therapy arms (dnase-discontinue - dnase-continue) in the absolute change in FEV1 % predicted from Week 0 to Week 6.	Week 0 to Week 6
Secondary	Incidence of Adverse Events (AEs) in Hypertonic Saline (Study A) Therapy Arms	Difference between hypertonic saline (HS) therapy arms (HS-discontinue - HS-continue) in the proportion of participants with at least one AE from Week 0 to Week 6.	Week 0 to Week 6
Secondary	Incidence of Adverse Events (AEs) in Dornase Alfa (Study B) Therapy Arms	Difference between dornase alfa (dnase) therapy arms (dnase-discontinue - dnase-continue) in the proportion of participants with at least one AE from Week 0 to Week 6.	Week 0 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 in Hypertonic Saline (Study A) Therapy Arms	Difference between hypertonic saline (HS) therapy arms (HS-discontinue - HS-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 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.	Week 0 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 in Dornase Alfa (Study B) Therapy Arms	Difference between dornase alfa (dnase) therapy arms (dnase-discontinue - dnase-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 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.	Week 0 to Week 6
Secondary	Absolute change in LCI 2.5 from Week 0 to Week 6 in Hypertonic Saline (Study A) Therapy Arms	Difference between hypertonic saline (HS) therapy arms (HS-discontinue - HS-continue) in the absolute change in LCI 2.5 (Lung Clearance Index) from Week 0 to Week 6.	Week 0 to Week 6
Secondary	Absolute change in LCI 2.5 from Week 0 to Week 6 in Dornase Alfa (Study B) Therapy Arms	Difference between dornase alfa (DA) therapy arms (DA-discontinue - DA-continue) in the absolute change in LCI 2.5 (Lung Clearance Index) from Week 0 to Week 6.	Week 0 to Week 6
Secondary	Absolute Change in Respiratory Symptoms, as Measured by CFQ-R Respiratory Domain from Week 0 to Week 6 in Hypertonic Saline (Study A) Therapy Arms	Difference between hypertonic saline (HS) therapy arms (HS-discontinue - HS-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 from 3 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.	Week 0 to Week 6
Secondary	Absolute Change in Respiratory Symptoms, as Measured by CFQ-R Respiratory Domain from Week 0 to Week 6 in Dornase Alfa (Study B) Therapy Arms	Difference between dornase alfa (DA) therapy arms (DA-discontinue - DA-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 from 3 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.	Week 0 to Week 6
Secondary	Absolute change in FEV1 % predicted from Week -2 to Week 0 in Hypertonic Saline (Study A) Therapy Arms	Difference between hypertonic saline (HS) therapy arms (HS-discontinue - HS-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 -2 to Week 0 in Dornase Alfa (Study B) Therapy Arms	Difference between dornase alfa (DA) therapy arms (DA-discontinue - DA-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 in Hypertonic Saline (Study A) Therapy Arms	Difference between hypertonic saline (HS) therapy arms (HS-discontinue - HS-continue) in the absolute change in FEV1 % predicted from Week 0 to Week 2.	Week 0 to Week 2
Secondary	Absolute change in FEV1 % predicted from Week 0 to Week 2 in Dornase Alfa (Study B) Therapy Arms	Difference between dornase alfa (DA) therapy arms (DA-discontinue - DA-continue) in the absolute change in FEV1 % predicted from Week 0 to Week 2.	Week 0 to Week 2
Secondary	Initiation of acute antibiotics from Week 0 to Week 6 in Hypertonic Saline (Study A) Therapy Arms	Difference between hypertonic saline (HS) therapy arms (HS-discontinue - HS-continue) in the percent of subjects initiating acute oral, inhaled or intravenous antibiotics from Week 0 to Week 6	Week 0 to Week 6
Secondary	Initiation of acute antibiotics from Week 0 to Week 6 in Dornase Alfa (Study B) Therapy Arms	Difference between dornase alfa (DA) therapy arms (DA-discontinue - DA-continue) in the percent of subjects initiating acute oral, inhaled or intravenous antibiotics from Week 0 to Week 6	Week 0 to Week 6
Secondary	Hospitalizations from Week 0 to Week 6 in Hypertonic Saline (Study A) Therapy Arms	Difference between hypertonic saline (HS) therapy arms (HS-discontinue - HS-continue) in the percent of subjects hospitalized from Week 0 to Week 6	Week 0 to Week 6
Secondary	Hospitalizations from Week 0 to Week 6 in Dornase Alfa (Study B) Therapy Arms	Difference between dornase alfa (DA) therapy arms (DA-discontinue - DA-continue) in the percent of subjects hospitalized from Week 0 to Week 6	Week 0 to Week 6
Secondary	Pulmonary Exacerbations from Week 0 to Week 6 in Hypertonic Saline (Study A) Therapy Arms	Difference between hypertonic saline (HS) therapy arms (HS-discontinue - HS-continue) in the percent of subjects experiencing a pulmonary exacerbation from Week 0 to Week 6	Week 0 to Week 6
Secondary	Pulmonary exacerbations from Week 0 to Week 6 in Dornase Alfa (Study B) Therapy Arms	Difference between dornase alfa (DA) therapy arms (DA-discontinue - DA-continue) in the percent of subjects experiencing a pulmonary exacerbation from Week 0 to Week 6	Week 0 to Week 6
Secondary	Adverse events from Week 0 to Week 6 in Hypertonic Saline (Study A) Therapy Arms	Difference between hypertonic saline (HS) therapy arms (HS-discontinue - HS-continue) in the percent of subjects experiencing an adverse event from Week 0 to Week 6	Week 0 to Week 6
Secondary	Adverse events from Week 0 to Week 6 in Dornase Alfa (Study B) Therapy Arms	Difference between dornase alfa (DA) therapy arms (DA-discontinue - DA-continue) in the percent of subjects experiencing an adverse event from Week 0 to Week 6	Week 0 to Week 6
Secondary	Temporary or permanent changes from assigned therapy regimen due to adverse event from Week 0 to Week 6 in Hypertonic Saline (Study A) Therapy Arms	Difference between hypertonic saline (HS) therapy arms (HS-discontinue - HS-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
Secondary	Temporary or permanent changes from assigned therapy regimen due to adverse event from Week 0 to Week 6 in Dornase Alfa (Study B) Therapy Arms	Difference between dornase alfa (DA) therapy arms (DA-discontinue - DA-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