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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

Tracking Information
First Submitted Date  ICMJE May 4, 2020
First Posted Date  ICMJE May 7, 2020
Last Update Posted Date May 8, 2020
Estimated Study Start Date  ICMJE July 15, 2020
Estimated Primary Completion Date May 31, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 4, 2020)
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 4, 2020)
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Impact of Discontinuing Chronic Therapies in People With Cystic Fibrosis on Highly Effective CFTR Modulator Therapy
Official Title  ICMJE A Master Protocol to Test the Impact of Discontinuing Chronic Therapies in People With Cystic Fibrosis on Highly Effective CFTR Modulator Therapy (SIMPLIFY)
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.

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
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Other
Condition  ICMJE Cystic Fibrosis
Intervention  ICMJE
  • Other: Discontinuation of hypertonic saline (HS)
    Discontinuation of current hypertonic saline (HS) therapy in Study A during 6-week study period.
  • 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%.
  • 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
  • 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
Study Arms  ICMJE
  • Experimental: HS-Discontinue (Study A)
    Discontinuation of current hypertonic saline (HS) therapy in Study A
    Intervention: Other: Discontinuation of hypertonic saline (HS)
  • Active Comparator: HS-Continue (Study A)
    Continuation of current hypertonic saline (HS) therapy in Study A
    Intervention: Other: Continuation of hypertonic saline (HS)
  • Experimental: Dnase-Discontinue (Study B)
    Discontinuation of current dornase alfa (dnase) therapy in Study B
    Intervention: Other: Discontinuation of dornase alfa (dnase)
  • Active Comparator: Dnase-Continue (Study B)
    Continuation of current dornase alfa (dnase) therapy in Study B
    Intervention: Other: Continuation of dornase alfa (dnase)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: May 4, 2020)
800
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 31, 2022
Estimated Primary Completion Date May 31, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Rachael Buckingham, BS 206-884-7517 rachael.buckingham@seattlechildrens.org
Contact: Anna Mead 884-7531 anna.mead@seattlechildrens.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04378153
Other Study ID Numbers  ICMJE SIMPLIFY-IP-19
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party David Nichols, MD, Seattle Children's Hospital
Study Sponsor  ICMJE David Nichols, MD
Collaborators  ICMJE
  • Cystic Fibrosis Foundation
  • Dartmouth-Hitchcock Medical Center
  • University of Washington
Investigators  ICMJE
Principal Investigator: Nicole Mayer-Hamblett, PhD University of Washington/Seattle Children's
Principal Investigator: Alex Gifford, MD, FCCP Dartmouth-Hitchcock Medical Center
PRS Account Seattle Children's Hospital
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP