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

Primary Purpose

Cystic Fibrosis

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
QR-010
Sponsored by
ProQR Therapeutics
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cystic Fibrosis focused on measuring Cystic Fibrosis, CF, ΔF508, CFTR, QR-010, antisense oligonucleotide, RNA therapy, F508del, NPD, nasal potential difference

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Alabama at Birmingham
  • National Jewish Health
  • Cincinnati Childrens Hospital Medical Center
  • U.Z. Leuven
  • Hopital Necker-Enfants Malades

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

ΔF508 Homozygous

ΔF508 Compound Heterozygous

Arm Description

QR-010 administered intranasally as an atomized liquid 10 mg (5 mg per nostril), 3 times weekly for 4 weeks.

QR-010 administered intranasally as an atomized liquid 10 mg (5 mg per nostril), 3 times weekly for 4 weeks.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Full Information

First Posted
September 29, 2015
Last Updated
September 2, 2020
Sponsor
ProQR Therapeutics
Collaborators
European Commission
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1. Study Identification

Unique Protocol Identification Number
NCT02564354
Brief Title
Exploratory Study to Evaluate QR-010 in Subjects With Cystic Fibrosis ΔF508 CFTR Mutation
Official Title
Open-Label, Exploratory Study to Evaluate the Effects of QR-010 on Nasal Potential Difference in Subjects With CF With the ΔF508 CFTR Mutation
Study Type
Interventional

2. Study Status

Record Verification Date
September 2020
Overall Recruitment Status
Completed
Study Start Date
September 2015 (undefined)
Primary Completion Date
September 2016 (Actual)
Study Completion Date
September 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
ProQR Therapeutics
Collaborators
European Commission

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cystic Fibrosis
Keywords
Cystic Fibrosis, CF, ΔF508, CFTR, QR-010, antisense oligonucleotide, RNA therapy, F508del, NPD, nasal potential difference

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Non-Randomized
Enrollment
18 (Actual)

8. Arms, Groups, and Interventions

Arm Title
ΔF508 Homozygous
Arm Type
Experimental
Arm Description
QR-010 administered intranasally as an atomized liquid 10 mg (5 mg per nostril), 3 times weekly for 4 weeks.
Arm Title
ΔF508 Compound Heterozygous
Arm Type
Experimental
Arm Description
QR-010 administered intranasally as an atomized liquid 10 mg (5 mg per nostril), 3 times weekly for 4 weeks.
Intervention Type
Drug
Intervention Name(s)
QR-010
Intervention Description
Single-stranded RNA antisense oligonucleotide in isoosmolar solution
Primary Outcome Measure Information:
Title
Intra-subject Change From Baseline of CFTR-mediated Total Chloride Transport as Measured by Nasal Potential Difference (NPD).
Description
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.
Secondary Outcome Measure Information:
Title
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.
Description
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.
Title
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.
Description
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.
Title
Intra-subject Change of Sodium Transport as Measured by Nasal Potential Difference (NPD) From Baseline Through End of Study.
Description
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.
Title
The Mean Change in CFTR-mediated Total Chloride Transport.
Description
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.
Title
Number of Subjects Experiencing Serious Adverse Events From Baseline Through End of Study.
Description
Number of subjects experiencing serious adverse events from baseline through End of Study.
Time Frame
3 weeks post-treatment.
Title
Number of Subject Discontinuations Due to AEs From Baseline Through End of Study.
Description
Number of subject discontinuations due to AEs from baseline through End of Study. No discontinuations occurred.
Time Frame
3 weeks post-treatment.
Title
Number of Subjects With Abnormalities of Laboratory Parameters From Baseline Through End of Study.
Description
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.
Title
Number of Subjects With Abnormalities of Vital Signs & Oximetry From Baseline Through End of Study.
Description
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.
Title
Number of Subjects With Abnormalities of Physical Examinations From Baseline Through End of Study.
Description
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.
Title
Changes in Nasal Symptoms (Based on the Nasal Examination Rating Scale - NERS) From Baseline Through End of Study.
Description
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.
Title
Changes in Nasal Symptoms (Sino-Nasal Outcome Test - SNOT-22) From Baseline Through End of Study.
Description
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.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John P Clancy, MD
Organizational Affiliation
Cincinnati Childrens Hospital Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35233
Country
United States
Facility Name
National Jewish Health
City
Denver
State/Province
Colorado
ZIP/Postal Code
80206
Country
United States
Facility Name
Cincinnati Childrens Hospital Medical Center
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
U.Z. Leuven
City
Leuven
ZIP/Postal Code
3000
Country
Belgium
Facility Name
Hopital Necker-Enfants Malades
City
Paris
ZIP/Postal Code
75743
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
31215818
Citation
Miah KM, Hyde SC, Gill DR. Emerging gene therapies for cystic fibrosis. Expert Rev Respir Med. 2019 Aug;13(8):709-725. doi: 10.1080/17476348.2019.1634547. Epub 2019 Jun 27.
Results Reference
derived

Learn more about this trial

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

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