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

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ClinicalTrials.gov Identifier: NCT04378153
Recruitment Status : Not yet recruiting
First Posted : May 7, 2020
Last Update Posted : May 8, 2020
Sponsor:
Collaborators:
Cystic Fibrosis Foundation
Dartmouth-Hitchcock Medical Center
University of Washington
Information provided by (Responsible Party):
David Nichols, MD, Seattle Children's Hospital

Brief 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.


Condition or disease Intervention/treatment Phase
Cystic Fibrosis Other: Discontinuation of hypertonic saline (HS) Other: Continuation of hypertonic saline (HS) Other: Discontinuation of dornase alfa (dnase) Other: Continuation of dornase alfa (dnase) Not Applicable

Detailed 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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 800 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
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)
Estimated Study Start Date : July 15, 2020
Estimated Primary Completion Date : May 31, 2022
Estimated Study Completion Date : May 31, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cystic Fibrosis

Arm Intervention/treatment
Experimental: HS-Discontinue (Study A)
Discontinuation of current hypertonic saline (HS) therapy in Study A
Other: Discontinuation of hypertonic saline (HS)
Discontinuation of current hypertonic saline (HS) therapy in Study A during 6-week study period.

Active Comparator: HS-Continue (Study A)
Continuation of current hypertonic saline (HS) therapy in Study A
Other: 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%.

Experimental: Dnase-Discontinue (Study B)
Discontinuation of current dornase alfa (dnase) therapy in Study B
Other: Discontinuation of dornase alfa (dnase)
Discontinuation of current dornase alfa (dnase) therapy in Study B during 6-week study period.
Other Name: Discontinuation of pulmozyme

Active Comparator: Dnase-Continue (Study B)
Continuation of current dornase alfa (dnase) therapy in Study B
Other: 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).
Other Name: Continuation of pulmozyme




Primary Outcome Measures :
  1. Absolute change in FEV1 % predicted from Week 0 to Week 6 in Hypertonic Saline (Study A) Therapy Arms [ Time Frame: Over the 6-week study period ]
    Difference between hypertonic saline (HS) therapy arms (HS-discontinue - HS-continue) in the absolute change in FEV1 % predicted from Week 0 to Week 6.

  2. Absolute change in FEV1 % predicted from Week 0 to Week 6 in Dornase Alfa (Study B) Therapy Arms [ Time Frame: Over the 6-week study period ]
    Difference between dornase alfa (dnase) therapy arms (dnase-discontinue - dnase-continue) in the absolute change in FEV1 % predicted from Week 0 to Week 6.


Secondary Outcome Measures :
  1. Incidence of Adverse Events (AEs) in Hypertonic Saline (Study A) Therapy Arms [ Time Frame: Over the 6-week study period ]
    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.

  2. Incidence of Adverse Events (AEs) in Dornase Alfa (Study B) Therapy Arms [ Time Frame: Over the 6-week study period ]
    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.

  3. 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 [ Time Frame: Over the 6-week study period ]
    Difference between hypertonic saline (HS) therapy arms (HS-discontinue - HS-continue) in the absolute change in respiratory symptoms, as measured by the 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.

  4. 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 [ Time Frame: Over the 6-week study period ]
    Difference between dornase alfa (dnase) therapy arms (dnase-discontinue - dnase-continue) in the absolute change in respiratory symptoms, as measured by the 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.



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Ages Eligible for Study:   12 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04378153


Contacts
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Contact: Rachael Buckingham, BS 206-884-7517 rachael.buckingham@seattlechildrens.org
Contact: Anna Mead 884-7531 anna.mead@seattlechildrens.org

Locations
Show Show 80 study locations
Sponsors and Collaborators
David Nichols, MD
Cystic Fibrosis Foundation
Dartmouth-Hitchcock Medical Center
University of Washington
Investigators
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Principal Investigator: Nicole Mayer-Hamblett, PhD University of Washington/Seattle Children's
Principal Investigator: Alex Gifford, MD, FCCP Dartmouth-Hitchcock Medical Center
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Responsible Party: David Nichols, MD, Associate Professor of Pediatrics, Seattle Children's Hospital
ClinicalTrials.gov Identifier: NCT04378153    
Other Study ID Numbers: SIMPLIFY-IP-19
First Posted: May 7, 2020    Key Record Dates
Last Update Posted: May 8, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by David Nichols, MD, Seattle Children's Hospital:
Cystic Fibrosis
CF
Withdrawal
Trikafta
hypertonic saline
dornase alfa
pulmozyme
Additional relevant MeSH terms:
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Cystic Fibrosis
Fibrosis
Pathologic Processes
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases