Trial Outcomes & Findings for Impact of Discontinuing Dornase Alfa in People With CF on Highly Effective CFTR Modulator Therapy-A SIMPLIFY Sub-Study (NCT NCT06350474)

NCT ID: NCT06350474

Last Updated: 2024-11-26

Results Overview

Non-Inferiority statistical testing compared difference between study arms (discontinue - continue) in the absolute change in FEV1 % predicted from Week 0 to Week 6.

• Recruitment status: COMPLETED
• Study phase: NA
• Target enrollment: 477 participants
• Primary outcome timeframe: Week 0 to Week 6
• Results posted on: 2024-11-26

Participant Flow

Participant milestones

Measure	Dnase - Discontinue Discontinuation of current dornase alfa (dnase) therapy Discontinuation of dornase alfa (Dnase): Discontinuation of current dornase alfa (Dnase) therapy during 6-week study period.	Dnase - Continue Continuation of current dornase alfa (dnase) therapy 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)
Overall Study STARTED	240	237
Overall Study COMPLETED	238	236
Overall Study NOT COMPLETED	2	1

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Dnase - Discontinue n=199 Participants Discontinuation of current dornase alfa (dnase) therapy Discontinuation of dornase alfa (Dnase): Discontinuation of current dornase alfa (Dnase) therapy during 6-week study period.	Dnase - Continue n=193 Participants Continuation of current dornase alfa (dnase) therapy 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)	Total n=392 Participants Total of all reporting groups
Age, Continuous	22.1 years STANDARD_DEVIATION 9.39 • n=5 Participants	23.7 years STANDARD_DEVIATION 11.83 • n=7 Participants	22.9 years STANDARD_DEVIATION 10.7 • n=5 Participants
Age, Customized Age Distribution (years) · >=12 to <18	89 Participants n=5 Participants	85 Participants n=7 Participants	174 Participants n=5 Participants
Age, Customized Age Distribution (years) · >=18 to <24	45 Participants n=5 Participants	36 Participants n=7 Participants	81 Participants n=5 Participants
Age, Customized Age Distribution (years) · >=24 to <30	25 Participants n=5 Participants	27 Participants n=7 Participants	52 Participants n=5 Participants
Age, Customized Age Distribution (years) · >=30	40 Participants n=5 Participants	45 Participants n=7 Participants	85 Participants n=5 Participants
Sex: Female, Male Female	98 Participants n=5 Participants	97 Participants n=7 Participants	195 Participants n=5 Participants
Sex: Female, Male Male	101 Participants n=5 Participants	96 Participants n=7 Participants	197 Participants n=5 Participants
Race/Ethnicity, Customized Race · White	192 Participants n=5 Participants	187 Participants n=7 Participants	379 Participants n=5 Participants
Race/Ethnicity, Customized Race · Black or African American	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Race/Ethnicity, Customized Race · Asian	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Race · American Indian or Alaskan Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Race · Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race/Ethnicity, Customized Race · Other, More than One Race, or Unknown/Not Reported	5 Participants n=5 Participants	2 Participants n=7 Participants	7 Participants n=5 Participants
Cystic Fibrosis (CF) Genotype F508del Homozygous	105 Participants n=5 Participants	115 Participants n=7 Participants	220 Participants n=5 Participants
Cystic Fibrosis (CF) Genotype F508del Heterozygous	90 Participants n=5 Participants	73 Participants n=7 Participants	163 Participants n=5 Participants
Cystic Fibrosis (CF) Genotype Other or Unknown	4 Participants n=5 Participants	5 Participants n=7 Participants	9 Participants n=5 Participants
Forced Expiratory Volume in 1 second (FEV1)	3.3 liters STANDARD_DEVIATION 0.88 • n=5 Participants	3.3 liters STANDARD_DEVIATION 0.86 • n=7 Participants	3.3 liters STANDARD_DEVIATION 0.87 • n=5 Participants
FEV1 (% Predicted)	96.8 percent predicted STANDARD_DEVIATION 17.40 • n=5 Participants	97.0 percent predicted STANDARD_DEVIATION 16.35 • n=7 Participants	96.9 percent predicted STANDARD_DEVIATION 16.87 • n=5 Participants
FEV1 (% Predicted) Distribution <60	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
FEV1 (% Predicted) Distribution >=60 to <70	16 Participants n=5 Participants	10 Participants n=7 Participants	26 Participants n=5 Participants
FEV1 (% Predicted) Distribution >=70 to <90	46 Participants n=5 Participants	48 Participants n=7 Participants	94 Participants n=5 Participants
FEV1 (% Predicted) Distribution >=90 to <100	42 Participants n=5 Participants	42 Participants n=7 Participants	84 Participants n=5 Participants
FEV1 (% Predicted) Distribution >=100	94 Participants n=5 Participants	90 Participants n=7 Participants	184 Participants n=5 Participants
Current Dornase Alfa Use	199 Participants n=5 Participants	193 Participants n=7 Participants	392 Participants n=5 Participants
Current Airway Clearance Use	187 Participants n=5 Participants	185 Participants n=7 Participants	372 Participants n=5 Participants

PRIMARY outcome

Timeframe: Week 0 to Week 6

Population: Per-protocol (PP) population.

Non-Inferiority statistical testing compared difference between study arms (discontinue - continue) in the absolute change in FEV1 % predicted from Week 0 to Week 6.

Outcome measures

Measure	Dnase - Discontinue n=199 Participants Discontinuation of dornase alfa (Dnase): Discontinuation of current dornase alfa (Dnase) therapy during 6-week study period.	Dnase - Continue n=193 Participants 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)
Absolute Change in FEV1 % Predicted From Week 0 to Week 6	0.2 FEV1 % predicted Standard Deviation 3.69	-0.2 FEV1 % predicted Standard Deviation 4.37

SECONDARY outcome

Timeframe: Baseline (Week 0 or Week -2) to Week 6

Population: Participants in the per-protocol (PP) population with an acceptable LCI 2.5 measurement at baseline and at Week 6.

Statistical testing compared 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.

Outcome measures

Measure	Dnase - Discontinue n=40 Participants Discontinuation of dornase alfa (Dnase): Discontinuation of current dornase alfa (Dnase) therapy during 6-week study period.	Dnase - Continue n=42 Participants 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)
Absolute Change in LCI 2.5 From Baseline to Week 6	-0.1 number of lung volume turnovers Standard Deviation 0.63	0.0 number of lung volume turnovers Standard Deviation 0.56

SECONDARY outcome

Timeframe: Week 0 to Week 6

Population: Participants in the per-protocol (PP) population with a CRISS score at Week 0 and at Week 6.

Statistical testing compared the 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

Outcome measures

Measure	Dnase - Discontinue n=199 Participants Discontinuation of dornase alfa (Dnase): Discontinuation of current dornase alfa (Dnase) therapy during 6-week study period.	Dnase - Continue n=193 Participants 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)
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	-0.1 score on a scale Standard Deviation 9.49	-1.1 score on a scale Standard Deviation 10.21

SECONDARY outcome

Timeframe: Week 0 to Week 6

Population: Participants in the per-protocol (PP) population with a score at Week 0 and at Week 6.

Statistical testing compared the 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.

Outcome measures

Measure	Dnase - Discontinue n=198 Participants Discontinuation of dornase alfa (Dnase): Discontinuation of current dornase alfa (Dnase) therapy during 6-week study period.	Dnase - Continue n=191 Participants 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)
Absolute Change in Respiratory Symptoms, as Measured by CFQ-R Respiratory Domain From Week 0 to Week 6	-0.9 score on a scale Standard Deviation 6.23	0.0 score on a scale Standard Deviation 8.85

SECONDARY outcome

Timeframe: Week -2 to Week 0

Population: Per-protocol (PP) population.

Statistical testing compared the difference between study arms (discontinue - continue) in the absolute change in FEV1 % predicted from Week -2 to Week 0.

Outcome measures

Measure	Dnase - Discontinue n=199 Participants Discontinuation of dornase alfa (Dnase): Discontinuation of current dornase alfa (Dnase) therapy during 6-week study period.	Dnase - Continue n=193 Participants 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)
Absolute Change in FEV1 % Predicted From Week -2 to Week 0	0.2 FEV1 % predicted Standard Deviation 3.11	0.0 FEV1 % predicted Standard Deviation 3.79

SECONDARY outcome

Timeframe: Week 0 to Week 2

Population: Participants in the per-protocol (PP) population with FEV1 measurements at Week 0 and at Week 2.

Statistical testing compared the difference between study arms (discontinue - continue) in the absolute change in FEV1 % predicted from Week 0 to Week 2.

Outcome measures

Measure	Dnase - Discontinue n=196 Participants Discontinuation of dornase alfa (Dnase): Discontinuation of current dornase alfa (Dnase) therapy during 6-week study period.	Dnase - Continue n=189 Participants 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)
Absolute Change in FEV1 % Predicted From Week 0 to Week 2	-0.1 FEV1 % predicted Standard Deviation 3.67	0.1 FEV1 % predicted Standard Deviation 3.96

SECONDARY outcome

Timeframe: Week 0 to Week 6

Population: Intent-to-treat (ITT) population of all randomized participants.

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.

Outcome measures

Measure	Dnase - Discontinue n=240 Participants Discontinuation of dornase alfa (Dnase): Discontinuation of current dornase alfa (Dnase) therapy during 6-week study period.	Dnase - Continue n=237 Participants 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)
Number and Percent of Participants Initiating Acute Antibiotics From Week 0 to Week 6	14 Participants	8 Participants

SECONDARY outcome

Timeframe: Week 0 to Week 6

Population: Intent-to-treat (ITT) population of all randomized participants.

Statistical testing compared the difference between study arms (discontinue - continue) in the percent of subjects hospitalized from Week 0 to Week 6.

Outcome measures

Measure	Dnase - Discontinue n=240 Participants Discontinuation of dornase alfa (Dnase): Discontinuation of current dornase alfa (Dnase) therapy during 6-week study period.	Dnase - Continue n=237 Participants 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)
Number and Percent of Participants Hospitalized From Week 0 to Week 6	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Week 0 to Week 6

Population: Intent-to-treat (ITT) population of all randomized participants.

Statistical testing compared the 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.

Outcome measures

Measure	Dnase - Discontinue n=240 Participants Discontinuation of dornase alfa (Dnase): Discontinuation of current dornase alfa (Dnase) therapy during 6-week study period.	Dnase - Continue n=237 Participants 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)
Number and Percent of Participants Experiencing Pulmonary Exacerbations From Week 0 to Week 6	4 Participants	2 Participants

SECONDARY outcome

Timeframe: Week 0 to Week 6

Statistical testing compared the 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.

Outcome measures

Measure	Dnase - Discontinue n=240 Participants Discontinuation of dornase alfa (Dnase): Discontinuation of current dornase alfa (Dnase) therapy during 6-week study period.	Dnase - Continue n=237 Participants 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)
Number and Percent of Participants Experiencing Adverse Events (AEs) From Week 0 to Week 6	89 Participants	55 Participants

SECONDARY outcome

Timeframe: Week 0 to Week 6

Population: Intent-to-treat (ITT) population of all randomized participants.

Statistical testing compared the compared the rate of AE occurrence (number of events divided by total follow-up weeks in each arm) between study arms from Week 0 to Week 6. Includes serious and non-serious AEs.

Outcome measures

Measure	Dnase - Discontinue n=240 Participants Discontinuation of dornase alfa (Dnase): Discontinuation of current dornase alfa (Dnase) therapy during 6-week study period.	Dnase - Continue n=237 Participants 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)
Rate of Adverse Events (AEs) From Week 0 to Week 6 Therapy Arms	0.116 events per week	0.060 events per week

SECONDARY outcome

Timeframe: Week 0 to Week 6

Population: Intent-to-treat (ITT) population of all randomized participants.

Statistical testing compared the 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

Outcome measures

Measure	Dnase - Discontinue n=240 Participants Discontinuation of dornase alfa (Dnase): Discontinuation of current dornase alfa (Dnase) therapy during 6-week study period.	Dnase - Continue n=237 Participants 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)
Number and Percent of Participants With Temporary or Permanent Changes From Assigned Therapy Regimen Due to Adverse Event From Week 0 to Week 6	7 Participants	2 Participants

Adverse Events

Dnase - Discontinue

Serious events: 0 serious events

Other events: 25 other events

Deaths: 0 deaths

Dnase - Continue

Serious events: 0 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Dnase - Discontinue n=240 participants at risk Discontinuation of dornase alfa (Dnase): Discontinuation of current dornase alfa (Dnase) therapy during 6-week study period.	Dnase - Continue n=237 participants at risk 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)
Respiratory, thoracic and mediastinal disorders Cough	6.7% 16/240 • Number of events 16 • From randomization (Week 0) up to last study visit (Week 6), i.e., 6 weeks.	4.2% 10/237 • Number of events 10 • From randomization (Week 0) up to last study visit (Week 6), i.e., 6 weeks.
Respiratory, thoracic and mediastinal disorders Nasal congestion	4.6% 11/240 • Number of events 12 • From randomization (Week 0) up to last study visit (Week 6), i.e., 6 weeks.	1.7% 4/237 • Number of events 4 • From randomization (Week 0) up to last study visit (Week 6), i.e., 6 weeks.

Additional Information

Margaret Kloster

Seattle Children's

Phone: 206-884-7862

Email: margaret.kloster@seattlechildrens.org

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place