Exploratory Study to Evaluate QR-010 in Subjects With Cystic Fibrosis ΔF508 CFTR Mutation

Study Overview
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Brief Summary
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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
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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.

Official Title
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Open-Label, Exploratory Study to Evaluate the Effects of QR-010 on Nasal Potential Difference in Subjects With CF With the ΔF508 CFTR Mutation

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: QR-010


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ΔF508 Homozygous<br>QR-010 administered intranasally as an atomized liquid 10 mg (5 mg per nostril), 3 times weekly for 4 weeks. | Drug: QR-010<br>* Single-stranded RNA antisense oligonucleotide in isoosmolar solution<br>|
| Experimental: ΔF508 Compound Heterozygous<br>QR-010 administered intranasally as an atomized liquid 10 mg (5 mg per nostril), 3 times weekly for 4 weeks. | Drug: QR-010<br>* Single-stranded RNA antisense oligonucleotide in isoosmolar solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, at 2 and 4 weeks, and at 3 weeks post-treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 2 and 4 weeks, and at 3 weeks post-treatment. | 
| 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. | 2 and 4 weeks, and at 3 weeks post-treatment. | 
| 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. | Baseline, at 2 and 4 weeks, and at 3 weeks post-treatment. | 
| 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. | 2 and 4 weeks, and at 3 weeks post-treatment. | 
| 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. | 3 weeks post-treatment. | 
| 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. | 3 weeks post-treatment. | 
| 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. | 3 weeks post-treatment. | 
| 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. | 3 weeks post-treatment. | 
| 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. | 3 weeks post-treatment. | 
| 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. | 3 weeks post-treatment. | 
| 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. | 3 weeks post-treatment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cystic Fibrosis, CF, ΔF508, CFTR, QR-010, antisense oligonucleotide, RNA therapy, F508del, NPD, nasal potential difference