Cystic Fibrosis
Conditions
Keywords
Cystic Fibrosis, CF, ΔF508, CFTR, QR-010, antisense oligonucleotide, RNA therapy, F508del, NPD, nasal potential difference
Brief summary
Exploratory proof of concept study to determine whether intranasal administration of QR-010 in subjects with cystic fibrosis, homozygous or compound heterozygous for the ΔF508 mutation, can increase the function of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR).
Detailed description
This is an open-label, multi-center, exploratory study to estimate the effect of intranasal administration of QR-010 on the nasal mucosa in the restoration of CFTR function, as measured by nasal potential difference (NPD), in the nasal epithelium of adult subjects with CF who are homozygous or compound heterozygous for the ΔF508 CFTR mutation.
Interventions
DRUGQR-010
Single-stranded RNA antisense oligonucleotide in isoosmolar solution
Sponsors
European Commission
ProQR Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Confirmed diagnosis of CF as defined by iontophoretic pilocarpine sweat chloride test (sweat chloride) of \> 60 mmol/L * Nasal potential difference (NPD) measurement at Screening consistent with CF * Confirmation of CFTR gene mutations homozygous or compound heterozygous for the ΔF508 mutation * Body mass index (BMI) of ≥ 18 kg/m2 * Non-smoking for a minimum of 2 years * Stable lung function * FEV1 ≥40% of predicted normal for age, gender, and height at Screening
Exclusion criteria
* Breast-feeding or pregnant * Acute allergy or infection affecting nasal conditions not resolved within 14 days prior Screening * Use of lumacaftor or ivacaftor * Use of any investigational drug or device * Hemoptysis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Intra-subject Change From Baseline of CFTR-mediated Total Chloride Transport as Measured by Nasal Potential Difference (NPD). | Baseline, at 2 and 4 weeks, and at 3 weeks post-treatment. | The primary endpoint was the within-subject change from baseline in total chloride transport as measured by NPD, after the Chloride-free+isoproterenol solution (Cl-free+iso), and was based on the average measurements of both nostrils. To provide baseline stability, baseline was defined as the average of the two most recent pre-dose values, where each pre-dose value was the average of two nostrils. A negative change from baseline of Cl-free+iso shows an improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With a -4 mV or More Negative Change in CFTR-mediated Total Chloride Transport, and After Different Treatment Durations From Baseline Through End of Study. | 2 and 4 weeks, and at 3 weeks post-treatment. | This analysis is the proportion of subjects with an average Cl-free+iso actual value of -4 mV or more negative after treatment (ie, responders), as measured by NPD and was based on the average measurements of both nostrils. The value of -4 mV is considered a clinically relevant response to treatment based on data from studies of other CFTR therapies. |
| Intra-subject Change of Sodium Transport as Measured by Nasal Potential Difference (NPD) From Baseline Through End of Study. | Baseline, at 2 and 4 weeks, and at 3 weeks post-treatment. | This endpoint was the within-subject change in Sodium transport (average Potential Difference prior to perfusion of any solution); this is the average of Potential Difference measured at five sites in the inferior meatus of the nose. A positive change from baseline shows an improvement. |
| The Mean Change in CFTR-mediated Total Chloride Transport. | 2 and 4 weeks, and at 3 weeks post-treatment. | The mean change in CFTR-mediated Total Chloride Transport compared to Baseline, per cohort; this is the mean of Potential Difference measured at five sites in the inferior meatus of the nose measured in millivolts (mV). A negative change from baseline shows an improvement. |
| Number of Subjects Experiencing Serious Adverse Events From Baseline Through End of Study. | 3 weeks post-treatment. | Number of subjects experiencing serious adverse events from baseline through End of Study. |
| Number of Subject Discontinuations Due to AEs From Baseline Through End of Study. | 3 weeks post-treatment. | Number of subject discontinuations due to AEs from baseline through End of Study. No discontinuations occurred. |
| Number of Subjects With a -6.6 mV or More Negative Change in CFTR-mediated Total Chloride Transport, and After Different Treatment Durations From Baseline Through End of Study. | 2 and 4 weeks, and at 3 weeks post-treatment. | This analysis is the proportion (amount) of subjects with an average Cl-free+iso actual value of -6.6 mV or more negative after treatment (ie, responders), as measured by NPD and was based on the average measurements of both nostrils. The actual value of -6.6 mV is used to discriminate individuals with CF (\>-6.6 mV) from normal individuals (≤ -6.6 mV). |
| Number of Subjects With Abnormalities of Vital Signs & Oximetry From Baseline Through End of Study. | 3 weeks post-treatment. | Number of subjects experiencing at least one abnormality vital signs & oximetry that were reported as treatment emergent adverse event with a relationship to study drug as either possibly, probably or definitely, from baseline through End of Study. |
| Number of Subjects With Abnormalities of Physical Examinations From Baseline Through End of Study. | 3 weeks post-treatment. | Number of subjects experiencing at least one abnormality in physical examination that were reported as treatment emergent adverse event with a relationship to study drug as either possibly, probably or definitely, from baseline through End of Study. |
| Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | 3 weeks post-treatment. | The NERS was performed by site staff prior to each dose and as part of the NPD procedure; it is a set of scales ranging from 0 (no symptoms) to 3 (most severe symptoms) for assessing the severity of each of the following nasal symptoms, separately for each nostril: mucosal disruption, edema, erythema, polyp, secretions. The range of the total sum is 0-30. |
| Changes in Nasal Symptoms (Sino-Nasal Outcome Test - SNOT-22) From Baseline Through End of Study. | 3 weeks post-treatment. | Subjects were asked to score a list of 22 symptoms on the SNOT-22 regarding social and emotional consequences. Outcomes were graded as 0 (no problem), to 5 (problem as bad as it could be). The list included: need to blow nose, sneezing, dripping nose, cough, postnasal drip, dense nasal drip, ear fullness, dizziness, ear pain, facial pain/pressure, difficulty falling asleep, waking at night, lack of a good night's sleep, waking up tired, fatigue, reduced productivity, reduced concentration, frustrated/restless/irritable, sad, embarrassed, decrease in smell and taste, and nasal obstruction. The range of the total sum is 0-110, with higher values indicating worse outcome. |
| Number of Subjects With Abnormalities of Laboratory Parameters From Baseline Through End of Study. | 3 weeks post-treatment. | Number of subjects experiencing at least one abnormality in laboratory parameters (chemistry, hematology and urinalysis) that were reported as treatment emergent adverse event with a relationship to study drug as either possibly, probably or definitely, from baseline through End of Study. |
Countries
Belgium, France, United States
Participant flow
Recruitment details
Subjects were screened and enrolled at 5 hospitals in the USA and Europe. Screenings for Cohort 1 and Cohort 2 occurred in parallel between between 19th October 2015 and 14th July 2016.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Homozygous for the F508del-CFTR Mutation Subjects homozygous for the F508del-CFTR mutation were enrolled into Cohort 1 and received QR-010 10 mg (5 mg/250 μL saline per nostril) via bilateral intranasal administration three times a week for 4 weeks for a total of 12 doses. | 10 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation Subjects compound heterozygous for the F508del-CFTR mutation were enrolled into Cohort 2 and received QR-010 10 mg (5 mg/250 μL saline per nostril) via bilateral intranasal administration three times a week for 4 weeks for a total of 12 doses. | 8 |
| Total | 18 |
Baseline characteristics
| Characteristic | Total | Cohort 1: Homozygous for the F508del-CFTR Mutation | Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 10 Participants | 8 Participants |
| Age, Continuous | 30.33 years | 25.80 years | 36.00 years |
| FEV1% predicted | 73.92 Percent of the predicted value | 74.22 Percent of the predicted value | 73.55 Percent of the predicted value |
| Region of Enrollment Belgium | 4 Participants | 2 Participants | 2 Participants |
| Region of Enrollment France | 5 Participants | 4 Participants | 1 Participants |
| Region of Enrollment United States | 9 Participants | 4 Participants | 5 Participants |
| Sex: Female, Male Female | 8 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Male | 10 Participants | 6 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 8 |
| other Total, other adverse events | 9 / 10 | 7 / 8 |
| serious Total, serious adverse events | 0 / 10 | 0 / 8 |
Outcome results
Primary
Intra-subject Change From Baseline of CFTR-mediated Total Chloride Transport as Measured by Nasal Potential Difference (NPD).
The primary endpoint was the within-subject change from baseline in total chloride transport as measured by NPD, after the Chloride-free+isoproterenol solution (Cl-free+iso), and was based on the average measurements of both nostrils. To provide baseline stability, baseline was defined as the average of the two most recent pre-dose values, where each pre-dose value was the average of two nostrils. A negative change from baseline of Cl-free+iso shows an improvement.
Time frame: Baseline, at 2 and 4 weeks, and at 3 weeks post-treatment.
Population: Per Protocol Set: 3 subjects from Cohort 1 and 1 subject from Cohort 2 didn't meet the NPD entry criterion and were excluded from the per protocol analysis. Further 1 subject from Cohort 1 did not have an interpretable Week 4 NPD measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Intra-subject Change From Baseline of CFTR-mediated Total Chloride Transport as Measured by Nasal Potential Difference (NPD). | Baseline | 1.86 mV | Standard Deviation 3.36 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Intra-subject Change From Baseline of CFTR-mediated Total Chloride Transport as Measured by Nasal Potential Difference (NPD). | Week 2 | -1.11 mV | Standard Deviation 8.062 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Intra-subject Change From Baseline of CFTR-mediated Total Chloride Transport as Measured by Nasal Potential Difference (NPD). | Week 4 | -1.92 mV | Standard Deviation 4.837 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Intra-subject Change From Baseline of CFTR-mediated Total Chloride Transport as Measured by Nasal Potential Difference (NPD). | 3 weeks post-treatment | -1.86 mV | Standard Deviation 6.736 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Intra-subject Change From Baseline of CFTR-mediated Total Chloride Transport as Measured by Nasal Potential Difference (NPD). | 3 weeks post-treatment | 2.27 mV | Standard Deviation 6.546 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Intra-subject Change From Baseline of CFTR-mediated Total Chloride Transport as Measured by Nasal Potential Difference (NPD). | Baseline | -0.75 mV | Standard Deviation 3.868 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Intra-subject Change From Baseline of CFTR-mediated Total Chloride Transport as Measured by Nasal Potential Difference (NPD). | Week 4 | 1.43 mV | Standard Deviation 2.644 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Intra-subject Change From Baseline of CFTR-mediated Total Chloride Transport as Measured by Nasal Potential Difference (NPD). | Week 2 | 1.66 mV | Standard Deviation 3.937 |
Secondary
Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study.
The NERS was performed by site staff prior to each dose and as part of the NPD procedure; it is a set of scales ranging from 0 (no symptoms) to 3 (most severe symptoms) for assessing the severity of each of the following nasal symptoms, separately for each nostril: mucosal disruption, edema, erythema, polyp, secretions. The range of the total sum is 0-30.
Time frame: 3 weeks post-treatment.
Population: Safety population: all subjects enrolled in the study. 1 measurement was missing from 1 subject in Cohort 2 for Week 4.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Week 4 | 13.00 units on a scale | Standard Deviation 2.828 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Day 12 | 11.50 units on a scale | Standard Deviation 1.269 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Day 5 | 11.50 units on a scale | Standard Deviation 1.65 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Week 2 | 12.50 units on a scale | Standard Deviation 2.635 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Day 17 | 11.20 units on a scale | Standard Deviation 2.098 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Day 24 | 11.90 units on a scale | Standard Deviation 2.378 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Day 19 | 11.90 units on a scale | Standard Deviation 2.183 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Week 1 | 12.60 units on a scale | Standard Deviation 2.171 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Week 3 | 13.10 units on a scale | Standard Deviation 2.685 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Day 3 | 11.60 units on a scale | Standard Deviation 1.647 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Day 10 | 11.50 units on a scale | Standard Deviation 1.9 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | 3 weeks post-treatment | 12.30 units on a scale | Standard Deviation 2.541 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Baseline | 12.20 units on a scale | Standard Deviation 1.317 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | 3 weeks post-treatment | 12.75 units on a scale | Standard Deviation 3.327 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Week 2 | 11.75 units on a scale | Standard Deviation 1.909 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Day 24 | 12.38 units on a scale | Standard Deviation 2.326 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Baseline | 11.50 units on a scale | Standard Deviation 1.773 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Day 3 | 13.38 units on a scale | Standard Deviation 3.335 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Day 5 | 12.25 units on a scale | Standard Deviation 2.55 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Week 1 | 12.00 units on a scale | Standard Deviation 1.852 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Day 10 | 11.88 units on a scale | Standard Deviation 2.532 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Day 12 | 11.50 units on a scale | Standard Deviation 1.414 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Day 17 | 12.00 units on a scale | Standard Deviation 2.878 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Day 19 | 11.63 units on a scale | Standard Deviation 1.923 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Week 3 | 12.63 units on a scale | Standard Deviation 2.134 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study. | Week 4 | 11.71 units on a scale | Standard Deviation 1.89 |
Secondary
Changes in Nasal Symptoms (Sino-Nasal Outcome Test - SNOT-22) From Baseline Through End of Study.
Subjects were asked to score a list of 22 symptoms on the SNOT-22 regarding social and emotional consequences. Outcomes were graded as 0 (no problem), to 5 (problem as bad as it could be). The list included: need to blow nose, sneezing, dripping nose, cough, postnasal drip, dense nasal drip, ear fullness, dizziness, ear pain, facial pain/pressure, difficulty falling asleep, waking at night, lack of a good night's sleep, waking up tired, fatigue, reduced productivity, reduced concentration, frustrated/restless/irritable, sad, embarrassed, decrease in smell and taste, and nasal obstruction. The range of the total sum is 0-110, with higher values indicating worse outcome.
Time frame: 3 weeks post-treatment.
Population: Safety population: all subjects enrolled in the study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Sino-Nasal Outcome Test - SNOT-22) From Baseline Through End of Study. | Week 2 | 13.60 units on a scale | Standard Deviation 8.369 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Sino-Nasal Outcome Test - SNOT-22) From Baseline Through End of Study. | Week 4 | 14.50 units on a scale | Standard Deviation 11.048 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Sino-Nasal Outcome Test - SNOT-22) From Baseline Through End of Study. | 3 weeks post-treatment | 10.70 units on a scale | Standard Deviation 8.301 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Sino-Nasal Outcome Test - SNOT-22) From Baseline Through End of Study. | Baseline | 14.90 units on a scale | Standard Deviation 5.896 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Sino-Nasal Outcome Test - SNOT-22) From Baseline Through End of Study. | 3 weeks post-treatment | 14.50 units on a scale | Standard Deviation 10.915 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Sino-Nasal Outcome Test - SNOT-22) From Baseline Through End of Study. | Week 2 | 15.38 units on a scale | Standard Deviation 18.601 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Sino-Nasal Outcome Test - SNOT-22) From Baseline Through End of Study. | Baseline | 19.13 units on a scale | Standard Deviation 17.707 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Changes in Nasal Symptoms (Sino-Nasal Outcome Test - SNOT-22) From Baseline Through End of Study. | Week 4 | 14.13 units on a scale | Standard Deviation 16.084 |
Secondary
Intra-subject Change of Sodium Transport as Measured by Nasal Potential Difference (NPD) From Baseline Through End of Study.
This endpoint was the within-subject change in Sodium transport (average Potential Difference prior to perfusion of any solution); this is the average of Potential Difference measured at five sites in the inferior meatus of the nose. A positive change from baseline shows an improvement.
Time frame: Baseline, at 2 and 4 weeks, and at 3 weeks post-treatment.
Population: Per Protocol Set: 3 subjects from Cohort 1 and 1 subject from Cohort 2 didn't meet the NPD entry criterion and were excluded from the per protocol analysis. Further 1 subject from Cohort 1 did not have an interpretable Week 4 NPD measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Intra-subject Change of Sodium Transport as Measured by Nasal Potential Difference (NPD) From Baseline Through End of Study. | Baseline | -31.92 mV | Standard Deviation 8.777 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Intra-subject Change of Sodium Transport as Measured by Nasal Potential Difference (NPD) From Baseline Through End of Study. | Week 2 | -33.80 mV | Standard Deviation 9.922 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Intra-subject Change of Sodium Transport as Measured by Nasal Potential Difference (NPD) From Baseline Through End of Study. | Week 4 | -25.14 mV | Standard Deviation 10.809 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Intra-subject Change of Sodium Transport as Measured by Nasal Potential Difference (NPD) From Baseline Through End of Study. | 3 weeks post-treatment | -31.56 mV | Standard Deviation 7.791 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Intra-subject Change of Sodium Transport as Measured by Nasal Potential Difference (NPD) From Baseline Through End of Study. | 3 weeks post-treatment | -27.59 mV | Standard Deviation 6.291 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Intra-subject Change of Sodium Transport as Measured by Nasal Potential Difference (NPD) From Baseline Through End of Study. | Baseline | -27.02 mV | Standard Deviation 11.412 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Intra-subject Change of Sodium Transport as Measured by Nasal Potential Difference (NPD) From Baseline Through End of Study. | Week 4 | -25.52 mV | Standard Deviation 10.445 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Intra-subject Change of Sodium Transport as Measured by Nasal Potential Difference (NPD) From Baseline Through End of Study. | Week 2 | -27.48 mV | Standard Deviation 9.23 |
Secondary
Number of Subject Discontinuations Due to AEs From Baseline Through End of Study.
Number of subject discontinuations due to AEs from baseline through End of Study. No discontinuations occurred.
Time frame: 3 weeks post-treatment.
Population: Safety population: all subjects enrolled in the study; incidence of discontinuations due to AEs from baseline through End of Study will be reported in the Adverse Events section. No discontinuations occurred.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Number of Subject Discontinuations Due to AEs From Baseline Through End of Study. | 0 Participants |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Number of Subject Discontinuations Due to AEs From Baseline Through End of Study. | 0 Participants |
Secondary
Number of Subjects Experiencing Serious Adverse Events From Baseline Through End of Study.
Number of subjects experiencing serious adverse events from baseline through End of Study.
Time frame: 3 weeks post-treatment.
Population: Safety population: all subjects enrolled in the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Number of Subjects Experiencing Serious Adverse Events From Baseline Through End of Study. | 0 Participants |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Number of Subjects Experiencing Serious Adverse Events From Baseline Through End of Study. | 0 Participants |
Secondary
Number of Subjects With a -4 mV or More Negative Change in CFTR-mediated Total Chloride Transport, and After Different Treatment Durations From Baseline Through End of Study.
This analysis is the proportion of subjects with an average Cl-free+iso actual value of -4 mV or more negative after treatment (ie, responders), as measured by NPD and was based on the average measurements of both nostrils. The value of -4 mV is considered a clinically relevant response to treatment based on data from studies of other CFTR therapies.
Time frame: 2 and 4 weeks, and at 3 weeks post-treatment.
Population: Per Protocol Set: 3 subjects from Cohort 1 and 1 subject from Cohort 2 didn't meet the NPD entry criterion and were excluded from the per protocol analysis. Further 1 subject from Cohort 1 did not have an interpretable Week 4 NPD measurement.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Number of Subjects With a -4 mV or More Negative Change in CFTR-mediated Total Chloride Transport, and After Different Treatment Durations From Baseline Through End of Study. | Week 4 | 2 Participants |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Number of Subjects With a -4 mV or More Negative Change in CFTR-mediated Total Chloride Transport, and After Different Treatment Durations From Baseline Through End of Study. | Week 2 | 3 Participants |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Number of Subjects With a -4 mV or More Negative Change in CFTR-mediated Total Chloride Transport, and After Different Treatment Durations From Baseline Through End of Study. | 3 weeks post-treatment | 4 Participants |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Number of Subjects With a -4 mV or More Negative Change in CFTR-mediated Total Chloride Transport, and After Different Treatment Durations From Baseline Through End of Study. | Week 2 | 1 Participants |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Number of Subjects With a -4 mV or More Negative Change in CFTR-mediated Total Chloride Transport, and After Different Treatment Durations From Baseline Through End of Study. | Week 4 | 1 Participants |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Number of Subjects With a -4 mV or More Negative Change in CFTR-mediated Total Chloride Transport, and After Different Treatment Durations From Baseline Through End of Study. | 3 weeks post-treatment | 0 Participants |
Secondary
Number of Subjects With a -6.6 mV or More Negative Change in CFTR-mediated Total Chloride Transport, and After Different Treatment Durations From Baseline Through End of Study.
This analysis is the proportion (amount) of subjects with an average Cl-free+iso actual value of -6.6 mV or more negative after treatment (ie, responders), as measured by NPD and was based on the average measurements of both nostrils. The actual value of -6.6 mV is used to discriminate individuals with CF (\>-6.6 mV) from normal individuals (≤ -6.6 mV).
Time frame: 2 and 4 weeks, and at 3 weeks post-treatment.
Population: Per Protocol Set: 3 subjects from Cohort 1 and 1 subject from Cohort 2 didn't meet the NPD entry criterion and were excluded from the per protocol analysis. Further 1 subject from Cohort 1 did not have an interpretable Week 4 NPD measurement.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Number of Subjects With a -6.6 mV or More Negative Change in CFTR-mediated Total Chloride Transport, and After Different Treatment Durations From Baseline Through End of Study. | Week 2 | 1 Participants |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Number of Subjects With a -6.6 mV or More Negative Change in CFTR-mediated Total Chloride Transport, and After Different Treatment Durations From Baseline Through End of Study. | Week 4 | 1 Participants |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Number of Subjects With a -6.6 mV or More Negative Change in CFTR-mediated Total Chloride Transport, and After Different Treatment Durations From Baseline Through End of Study. | 3 weeks post-treatment | 2 Participants |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Number of Subjects With a -6.6 mV or More Negative Change in CFTR-mediated Total Chloride Transport, and After Different Treatment Durations From Baseline Through End of Study. | Week 2 | 0 Participants |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Number of Subjects With a -6.6 mV or More Negative Change in CFTR-mediated Total Chloride Transport, and After Different Treatment Durations From Baseline Through End of Study. | Week 4 | 0 Participants |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Number of Subjects With a -6.6 mV or More Negative Change in CFTR-mediated Total Chloride Transport, and After Different Treatment Durations From Baseline Through End of Study. | 3 weeks post-treatment | 0 Participants |
Secondary
Number of Subjects With Abnormalities of Laboratory Parameters From Baseline Through End of Study.
Number of subjects experiencing at least one abnormality in laboratory parameters (chemistry, hematology and urinalysis) that were reported as treatment emergent adverse event with a relationship to study drug as either possibly, probably or definitely, from baseline through End of Study.
Time frame: 3 weeks post-treatment.
Population: Safety population: all subjects enrolled in the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Number of Subjects With Abnormalities of Laboratory Parameters From Baseline Through End of Study. | 0 Participants |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Number of Subjects With Abnormalities of Laboratory Parameters From Baseline Through End of Study. | 0 Participants |
Secondary
Number of Subjects With Abnormalities of Physical Examinations From Baseline Through End of Study.
Number of subjects experiencing at least one abnormality in physical examination that were reported as treatment emergent adverse event with a relationship to study drug as either possibly, probably or definitely, from baseline through End of Study.
Time frame: 3 weeks post-treatment.
Population: Safety population: all subjects enrolled in the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Number of Subjects With Abnormalities of Physical Examinations From Baseline Through End of Study. | 3 Participants |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Number of Subjects With Abnormalities of Physical Examinations From Baseline Through End of Study. | 4 Participants |
Secondary
Number of Subjects With Abnormalities of Vital Signs & Oximetry From Baseline Through End of Study.
Number of subjects experiencing at least one abnormality vital signs & oximetry that were reported as treatment emergent adverse event with a relationship to study drug as either possibly, probably or definitely, from baseline through End of Study.
Time frame: 3 weeks post-treatment.
Population: Safety population: all subjects enrolled in the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Homozygous for the F508del-CFTR Mutation | Number of Subjects With Abnormalities of Vital Signs & Oximetry From Baseline Through End of Study. | 0 Participants |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | Number of Subjects With Abnormalities of Vital Signs & Oximetry From Baseline Through End of Study. | 0 Participants |
Secondary
The Mean Change in CFTR-mediated Total Chloride Transport.
The mean change in CFTR-mediated Total Chloride Transport compared to Baseline, per cohort; this is the mean of Potential Difference measured at five sites in the inferior meatus of the nose measured in millivolts (mV). A negative change from baseline shows an improvement.
Time frame: 2 and 4 weeks, and at 3 weeks post-treatment.
Population: Per Protocol Set: 3 subjects from Cohort 1 and 1 subject from Cohort 2 didn't meet the NPD entry criterion and were excluded from the per protocol analysis. Further 1 subject from Cohort 1 did not have an interpretable Week 4 NPD measurement.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1: Homozygous for the F508del-CFTR Mutation | The Mean Change in CFTR-mediated Total Chloride Transport. | Week 2 | -2.44 mV | Standard Error 2 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | The Mean Change in CFTR-mediated Total Chloride Transport. | Week 4 | -3.46 mV | Standard Error 1.88 |
| Cohort 1: Homozygous for the F508del-CFTR Mutation | The Mean Change in CFTR-mediated Total Chloride Transport. | 3 weeks post-treatment | -3.19 mV | Standard Error 2.26 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | The Mean Change in CFTR-mediated Total Chloride Transport. | Week 2 | 1.88 mV | Standard Error 2 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | The Mean Change in CFTR-mediated Total Chloride Transport. | Week 4 | 1.65 mV | Standard Error 1.7 |
| Cohort 2: Compound Heterozygous for the F508del-CFTR Mutation | The Mean Change in CFTR-mediated Total Chloride Transport. | 3 weeks post-treatment | 2.49 mV | Standard Error 2.26 |