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

Study Overview
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Brief Summary
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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.

Detailed Description
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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

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

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Other: Discontinuation of hypertonic saline (HS)
* Other: Continuation of hypertonic saline (HS)
* Other: Discontinuation of dornase alfa (dnase)
* Other: Continuation of dornase alfa (dnase)


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HS-Discontinue (Study A)<br>Discontinuation of current hypertonic saline (HS) therapy in Study A | Other: Discontinuation of hypertonic saline (HS)<br>* Discontinuation of current hypertonic saline (HS) therapy in Study A during 6-week study period.<br>|
| Active Comparator: HS-Continue (Study A)<br>Continuation of current hypertonic saline (HS) therapy in Study A | Other: Continuation of hypertonic saline (HS)<br>* 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%.<br>|
| Experimental: Dnase-Discontinue (Study B)<br>Discontinuation of current dornase alfa (dnase) therapy in Study B | Other: Discontinuation of dornase alfa (dnase)<br>* Discontinuation of current dornase alfa (dnase) therapy in Study B during 6-week study period.<br>* Other names: Discontinuation of pulmozyme;|
| Active Comparator: Dnase-Continue (Study B)<br>Continuation of current dornase alfa (dnase) therapy in Study B | Other: Continuation of dornase alfa (dnase)<br>* 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).<br>* Other names: Continuation of pulmozyme;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cystic Fibrosis, CF, Withdrawal, Trikafta, hypertonic saline, dornase alfa, pulmozyme