Dose Escalation Study of QR-010 in Homozygous ΔF508 Cystic Fibrosis Patients
Sponsor
ProQR Therapeutics (Industry)
Overall Status
Completed
CT.gov ID
NCT02532764
Collaborator
European Commission (Other)
70
27
2
27.5
2.6
0.1
Study Details
Study Description
Brief Summary
A randomized, double-blind, placebo-controlled study of single and multiple ascending doses of QR-010 in adults homozygous for ΔF508 Cystic Fibrosis.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1/Phase 2 |
Detailed Description
The purpose of this study is to evaluate the safety, tolerability, and to determine the pharmacokinetics of QR-010 administered via inhalation in adult homozygous for ΔF508 Cystic Fibrosis.
Study Design
Study Type:
Interventional
Actual Enrollment
:
70 participants
Allocation:
Randomized
Intervention Model:
Single Group Assignment
Masking:
Triple (Participant, Care Provider, Investigator)
Primary Purpose:
Treatment
Official Title:
Phase 1b, Randomized, Double-blind, Placebo-controlled, Dose Escalation Study to Evaluate the Safety, Tolerability and Pharmacokinetics of QR-010 in Subjects With Homozygous ΔF508 Cystic Fibrosis
Study Start Date
:
Jun 1, 2015
Actual Primary Completion Date
:
Sep 14, 2017
Actual Study Completion Date
:
Sep 14, 2017
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: QR-010 QR-010 administered via inhalation either as a single dose or three times weekly for four weeks. |
Drug: QR-010
Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton
|
| Placebo Comparator: Placebo Placebo (normal saline) administered via inhalation either as a single dose or three times weekly for four weeks. |
Drug: Placebo
Normal Saline
|
Outcome Measures
Primary Outcome Measures
- Incidence of Subjects Experiencing Treatment Emergent Adverse Events From Baseline Through End of Study [8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts]
Number of subjects experiencing at least one treatment emergent adverse events (TEAEs)
- Severity of Treatment Emergent Adverse Events From Baseline Through End of Study [8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts]
Assessment of severity of treatment emergent adverse events (TEAEs). Severity is graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Modified for CF (CTCAE v4.03). For events not present in this listing the following grading was applied: Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; Moderate: Minimal, local, or noninvasive intervention indicated; discomfort sufficient to reduce or interfere with daily activities; Severe: Medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization may be indicated; disabling; limits self-care with significant interference with daily activities; incapacitating with inability to perform self care activities of daily living; Life-threatening: Urgent intervention indicated; immediate risk of death.
- Incidence of Subjects Experiencing Dose-Limiting Toxicities (DLT) in Each Dose Cohort From Baseline Through End of Study Visit. [8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts]
DLT's were defined as an allergic reaction, acute bronchospasm or acute AEs of interest requiring (immediate) medical intervention.
Secondary Outcome Measures
- Number of Subjects With Abnormalities Reported Regarding Laboratory Parameters, Vital Signs, ECG, Spirometry, and Physical Findings. [8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts]
Number of subjects experiencing at least one abnormality for the categories laboratory parameters, vital signs, ECG, spirometry and physical findings that were reported as treatment emergent adverse event with a relationship to study drug as either possibly, probably or definitely.
- Maximum Serum Concentration [8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts]
Cmax: QR-010 maximum serum concentrations
- Time to Maximum Serum Concentration [8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts]
Tmax: Time to Cmax of QR-010 serum concentrations.
- Terminal Half-life (T1/2) [8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts]
The terminal elimination half-life will be estimated by non-linear regression analysis of the terminal elimination slope
- Area Under the Curve to Final Sample [AUC(0-last)] [8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts]
Area under the curve to the final sample with a concentration greater than lower limit of quantification (LLQ) will be calculated using the linear trapezoidal method
- Area Under the Curve to Infinity [AUC(0-∞)] [8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts]
AUC0-∞: Area under the curve to infinity will be calculated based on the last observed concentration Clast(obs) using formula: AUC0-∞=AUClast+Clast(obs)/λz
- Serum Clearance (CL) [8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts]
CL: Serum clearance will be estimated using the formula: CL = Dose/AUC0-∞.
Other Outcome Measures
- Adjusted Mean Change From Baseline in CFQ-R RSS [Day 15, Day 33, Day 54]
Patient Reported Outcome measure Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Score (CFQ-R RSS). A higher score represents a better outcome. A minimal clinically important difference (MCID) in the respiratory domain (CFQ-R RSS) has been established in stable populations as 4.0 points, and a maximum score is 100 points. Mean values reported refer to ''adjusted mean change from baseline'' values.
- Adjusted Mean Change From Baseline in CFQ-R RSS as Compared to Placebo [Day 15, Day 33, Day 54]
Patient Reported Outcome measure Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Score (CFQ-R RSS). A higher score represents a better outcome. A minimal clinically important difference (MCID) in the respiratory domain (CFQ-R RSS) has been established in stable populations as 4.0 points, and a maximum score is 100 points. Mean values reported refer to ''adjusted mean change from baseline'' values.
- Adjusted Mean Change From Baseline in CFQ-R RSS (Subgroup ppFEV1 <90% at Baseline) [Day 15, Day 33, Day 54]
Patient Reported Outcome measure Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Score (CFQ-R RSS). A higher score represents a better outcome. A minimal clinically important difference (MCID) in the respiratory domain (CFQ-R RSS) has been established in stable populations as 4.0 points, and a maximum score is 100 points. Mean values reported refer to ''adjusted mean change from baseline'' values.
- Adjusted Mean Change From Baseline in CFQ-R RSS as Compared to Placebo (Subgroup ppFEV1 <90% at Baseline) [Day 15, Day 33, Day 54]
Patient Reported Outcome measure Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Score (CFQ-R RSS). A higher score represents a better outcome. A minimal clinically important difference (MCID) in the respiratory domain (CFQ-R RSS) has been established in stable populations as 4.0 points, and a maximum score is 100 points. Mean values reported refer to ''difference vs placebo in adjusted mean change from baseline'' values.
- Adjusted Mean Change From Baseline in ppFEV1 [Day 15, Day 33, Day 54]
Exploratory efficacy parameter, as measured by spirometry, and expressed in percent predicted FEV1 (ppFEV1). Mean values reported refer to ''adjusted mean change from baseline'' values.
- Adjusted Mean Change From Baseline in ppFEV1 as Compared to Placebo [Day 15, Day 33, Day 54]
Exploratory efficacy parameter, as measured by spirometry, and expresssed in percent predicted FEV1 (ppFEV1). Mean values reported refer to''difference vs placebo in adjusted mean change from baseline'' values.
- Adjusted Mean Change From Baseline in ppFEV1 (Subgroup ppFEV1 <90% at Baseline) [Day 15, Day 33, Day 54]
Exploratory efficacy parameter, as measured by spirometry, and expresssed in percent predicted FEV1. Mean values reported refer to ''adjusted mean change from baseline'' values.
- Adjusted Mean Change From Baseline in ppFEV1 as Compared to Placebo (Subgroup ppFEV1 <90% at Baseline) [Day 15, Day 33, Day 54]
Exploratory efficacy parameter, as measured by spirometry, and expresssed in percent predicted FEV1. Mean values reported refer to ''difference vs placebo in adjusted mean change from baseline'' values.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 60 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:
-
Confirmed diagnosis of CF as defined by iontophoretic pilocarpine sweat chloride test (sweat chloride) of > 60 mmol/L
-
Confirmation of CFTR gene mutations homozygous for the ΔF508 mutation
-
Body mass index (BMI) ≥ 17 kg/m2
-
Non-smoking for a minimum of two years
-
FEV1 ≥70% of predicted normal for age, gender, and height, at Screening
-
Stable lung function
-
Adequate hepatic and renal function
Exclusion Criteria:
-
Breast-feeding or pregnant
-
Use of lumacaftor or ivacaftor
-
Use of any investigational drug or device
-
History of lung transplantation
-
Hemoptysis
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University of Southern California USC - Keck School of Medicine | Los Angeles | California | United States | 90033 |
| 2 | Stanford University | Palo Alto | California | United States | 940304 |
| 3 | Northwestern University | Chicago | Illinois | United States | 60611 |
| 4 | University of Kansas Medical Center Research Institute | Kansas City | Kansas | United States | 66160 |
| 5 | Massachusetts General Hospital | Boston | Massachusetts | United States | 02114 |
| 6 | Boston Children's Hospital | Boston | Massachusetts | United States | 02115 |
| 7 | Washington University School of Medicine | Saint Louis | Missouri | United States | 63110-1032 |
| 8 | Nationwide Children's Hospital | Columbus | Ohio | United States | 66160 |
| 9 | Penn State Milton S. Hershey Medical Center | Hershey | Pennsylvania | United States | 17033 |
| 10 | Medical University of South Carolina | Charleston | South Carolina | United States | 29425 |
| 11 | University of Texas Southwestern Medical Center | Dallas | Texas | United States | 75390 |
| 12 | University of Washington Medical Center | Seattle | Washington | United States | 98195-6522 |
| 13 | Universitair Ziekenhuis Brussel | Brussels | Belgium | 01090 | |
| 14 | University of Leuven | Leuven | Belgium | 03000 | |
| 15 | University of Calgary (Health Sciences Centre) | Calgary | Alberta | Canada | T2N 4N1 |
| 16 | Motol University Hospital | Prague | Czechia | 15006 | |
| 17 | Cystic Fibrosis Center Rigshospitalet | Copenhagen | Denmark | 02100 | |
| 18 | HGRL Chu Nantes | Nantes | France | 44300 | |
| 19 | Hopital Necker- Enfants Malades | Paris | France | 75743 | |
| 20 | Charité Universitätsmedizin Berlin | Berlin | Germany | 13353 | |
| 21 | Medizinische Hochschule Hannover | Hannover | Germany | 30625 | |
| 22 | Munich U. Hospital, Cystic Fibrosis Center for Adults | Munich | Germany | 80336 | |
| 23 | Azienda Ospedaliera Universitaria Integrata di Verona | Verona | Italy | 37134 | |
| 24 | Hospital Vall D'Hebron | Barcelona | Spain | 08035 | |
| 25 | Celerion | Belfast | Northern Ireland | United Kingdom | BT9 6AD |
| 26 | Royal Brompton Hospital | London | United Kingdom | SW3 6NP | |
| 27 | Southampton General Hospital | Southampton | United Kingdom | SO16 6YD |
Sponsors and Collaborators
- ProQR Therapeutics
- European Commission
Investigators
- Principal Investigator: Stuart Elborn, MD, Trust and Queen's University Belfast
Study Documents (Full-Text)
More Information
Publications
None provided.Responsible Party:
ProQR Therapeutics
ClinicalTrials.gov Identifier:
NCT02532764
Other Study ID Numbers:
- PQ-010-001
First Posted:
Aug 26, 2015
Last Update Posted:
Feb 6, 2019
Last Verified:
Jan 1, 2019
Keywords provided by ProQR Therapeutics
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | The enrollment of this clinical trial followed a staggered approach; a new SAD cohort was enrolled following review of the previous SAD cohort. The first MAD cohort opened following the review of the first two SAD cohorts. Subsequent MAD dosing cohorts were initiated following review of the corresponding supportive SAD and MAD cohorts. |
|---|---|
| Pre-assignment Detail |
| Arm/Group Title | QR-010 SAD 6.25mg | QR-010 SAD 12.5 mg | QR-010 SAD 25 mg | QR-010 SAD 50 mg | Placebo SAD | QR-010 MAD 6.25 | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg | Placebo MAD |
|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | QR-010 administered via inhalation as a single dose. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalation | QR-010 administered via inhalation as a single dose. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalation | QR-010 administered via inhalation as a single dose. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalation | QR-010 administered via inhalation as a single dose. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalation | Placebo (normal saline) administered via inhalation as a single dose Placebo: Normal Saline | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalation. | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalation. | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalation. | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalation. | Placebo (normal saline) administered via inhalation three times weekly for four weeks. Placebo: Normal Saline |
| Period Title: Single Ascending Dose (SAD) Cohorts | ||||||||||
| STARTED | 6 | 6 | 9 | 6 | 9 | 0 | 0 | 0 | 0 | 0 |
| COMPLETED | 6 | 6 | 9 | 6 | 9 | 0 | 0 | 0 | 0 | 0 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Period Title: Single Ascending Dose (SAD) Cohorts | ||||||||||
| STARTED | 0 | 0 | 0 | 0 | 0 | 6 | 6 | 7 | 6 | 9 |
| COMPLETED | 0 | 0 | 0 | 0 | 0 | 6 | 6 | 6 | 5 | 8 |
| NOT COMPLETED | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 1 | 1 |
Baseline Characteristics
| Arm/Group Title | QR-010 SAD 6.25 mg | QR-010 SAD 12.5 mg | QR-010 SAD 25 mg | QR-010 SAD 50 mg | Placebo SAD | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg | Placebo MAD | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation as a single dose Placebo: Normal Saline | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation three times weekly for four weeks. Placebo: Normal Saline | Total of all reporting groups |
| Overall Participants | 6 | 6 | 9 | 6 | 9 | 6 | 6 | 7 | 6 | 9 | 70 |
| Age (Count of Participants) | |||||||||||
| <=18 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Between 18 and 65 years |
6
100%
|
6
100%
|
9
100%
|
6
100%
|
9
100%
|
6
100%
|
6
100%
|
7
100%
|
6
100%
|
9
100%
|
70
100%
|
| >=65 years |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Age (years) [Mean (Standard Deviation) ] | |||||||||||
| Mean (Standard Deviation) [years] |
25.8
(8.01)
|
21.5
(2.95)
|
27.2
(7.31)
|
22.7
(3.88)
|
24.8
(8.26)
|
22.7
(2.66)
|
27.7
(10.42)
|
32.3
(10.63)
|
23.3
(4.18)
|
26.3
(6.69)
|
25.6
(7.35)
|
| Sex: Female, Male (Count of Participants) | |||||||||||
| Female |
4
66.7%
|
5
83.3%
|
5
55.6%
|
2
33.3%
|
3
33.3%
|
3
50%
|
3
50%
|
5
71.4%
|
2
33.3%
|
6
66.7%
|
38
54.3%
|
| Male |
2
33.3%
|
1
16.7%
|
4
44.4%
|
4
66.7%
|
6
66.7%
|
3
50%
|
3
50%
|
2
28.6%
|
4
66.7%
|
3
33.3%
|
32
45.7%
|
| Race (NIH/OMB) (Count of Participants) | |||||||||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| White |
6
100%
|
6
100%
|
9
100%
|
6
100%
|
9
100%
|
6
100%
|
6
100%
|
7
100%
|
6
100%
|
9
100%
|
70
100%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (participants) [Number] | |||||||||||
| Canada |
0
0%
|
0
0%
|
2
22.2%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
14.3%
|
0
0%
|
0
0%
|
3
4.3%
|
| Belgium |
1
16.7%
|
1
16.7%
|
0
0%
|
0
0%
|
2
22.2%
|
1
16.7%
|
1
16.7%
|
0
0%
|
1
16.7%
|
2
22.2%
|
9
12.9%
|
| United States |
1
16.7%
|
1
16.7%
|
4
44.4%
|
5
83.3%
|
1
11.1%
|
1
16.7%
|
1
16.7%
|
0
0%
|
1
16.7%
|
3
33.3%
|
18
25.7%
|
| Czechia |
2
33.3%
|
2
33.3%
|
0
0%
|
0
0%
|
2
22.2%
|
0
0%
|
2
33.3%
|
0
0%
|
1
16.7%
|
0
0%
|
9
12.9%
|
| Denmark |
0
0%
|
0
0%
|
1
11.1%
|
0
0%
|
2
22.2%
|
1
16.7%
|
0
0%
|
2
28.6%
|
1
16.7%
|
1
11.1%
|
8
11.4%
|
| Italy |
1
16.7%
|
1
16.7%
|
0
0%
|
0
0%
|
2
22.2%
|
1
16.7%
|
1
16.7%
|
1
14.3%
|
0
0%
|
0
0%
|
7
10%
|
| United Kingdom |
1
16.7%
|
0
0%
|
1
11.1%
|
1
16.7%
|
0
0%
|
1
16.7%
|
0
0%
|
0
0%
|
1
16.7%
|
3
33.3%
|
8
11.4%
|
| France |
0
0%
|
0
0%
|
1
11.1%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
14.3%
|
0
0%
|
0
0%
|
2
2.9%
|
| Germany |
0
0%
|
1
16.7%
|
0
0%
|
0
0%
|
0
0%
|
1
16.7%
|
1
16.7%
|
2
28.6%
|
1
16.7%
|
0
0%
|
6
8.6%
|
| Weight (kg) (kg) [Mean (Standard Deviation) ] | |||||||||||
| Mean (Standard Deviation) [kg] |
59.4
(9.28)
|
64.8
(2.26)
|
67.5
(13.00)
|
57.7
(9.70)
|
62.2
(6.48)
|
66.8
(6.87)
|
62.6
(8.97)
|
67.1
(4.35)
|
61.3
(13.37)
|
59.6
(9.19)
|
63.0
(9.11)
|
| BMI (kg/m2) [Mean (Standard Deviation) ] | |||||||||||
| Mean (Standard Deviation) [kg/m2] |
22.1
(2.54)
|
24.1
(2.33)
|
23.0
(2.59)
|
21.5
(2.91)
|
21.4
(1.73)
|
23.5
(2.76)
|
22.8
(2.65)
|
23.6
(1.56)
|
21.3
(2.86)
|
20.9
(1.56)
|
22.3
(2.42)
|
| FEV1 (L) [Mean (Standard Deviation) ] | |||||||||||
| Mean (Standard Deviation) [L] |
3.24
(0.877)
|
3.15
(0.666)
|
3.78
(1.092)
|
3.06
(0.700)
|
3.64
(0.748)
|
3.49
(0.590)
|
3.19
(0.600)
|
2.85
(0.577)
|
3.40
(0.993)
|
3.18
(0.778)
|
3.32
(0.792)
|
| ppFEV1 (percent) [Mean (Standard Deviation) ] | |||||||||||
| Mean (Standard Deviation) [percent] |
92.3
(13.31)
|
91.4
(19.93)
|
97.3
(20.39)
|
80.9
(8.99)
|
91.8
(12.91)
|
90.7
(14.28)
|
89.0
(14.21)
|
79.9
(10.14)
|
84.7
(13.59)
|
86.7
(11.91)
|
88.8
(14.54)
|
Outcome Measures
| Title | Incidence of Subjects Experiencing Treatment Emergent Adverse Events From Baseline Through End of Study |
|---|---|
| Description | Number of subjects experiencing at least one treatment emergent adverse events (TEAEs) |
| Time Frame | 8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts |
Outcome Measure Data
| Analysis Population Description |
|---|
| All subjects who received either QR-010 or placebo |
| Arm/Group Title | QR-010 SAD 6.25 mg | QR-010 SAD 12.5 mg | QR-010 SAD 25 mg | QR-010 SAD 50 mg | Placebo SAD | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg | Placebo MAD |
|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation as a single dose Placebo: Normal Saline | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation three times weekly for four weeks. Placebo: Normal Saline |
| Measure Participants | 6 | 6 | 9 | 6 | 9 | 6 | 6 | 7 | 6 | 9 |
| Count of Participants [Participants] |
3
50%
|
2
33.3%
|
7
77.8%
|
4
66.7%
|
2
22.2%
|
5
83.3%
|
5
83.3%
|
6
85.7%
|
5
83.3%
|
9
100%
|
| Title | Severity of Treatment Emergent Adverse Events From Baseline Through End of Study |
|---|---|
| Description | Assessment of severity of treatment emergent adverse events (TEAEs). Severity is graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events Modified for CF (CTCAE v4.03). For events not present in this listing the following grading was applied: Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated; Moderate: Minimal, local, or noninvasive intervention indicated; discomfort sufficient to reduce or interfere with daily activities; Severe: Medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization may be indicated; disabling; limits self-care with significant interference with daily activities; incapacitating with inability to perform self care activities of daily living; Life-threatening: Urgent intervention indicated; immediate risk of death. |
| Time Frame | 8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts |
Outcome Measure Data
| Analysis Population Description |
|---|
| All subjects who received either QR-010 or placebo. |
| Arm/Group Title | QR-010 SAD 6.25 mg | QR-010 SAD 12.5 mg | QR-010 SAD 25 mg | QR-010 SAD 50 mg | Placebo SAD | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg | Placebo MAD |
|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation as a single dose Placebo: Normal Saline | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation three times weekly for four weeks. Placebo: Normal Saline |
| Measure Participants | 6 | 6 | 9 | 6 | 9 | 6 | 6 | 7 | 6 | 9 |
| Mild |
3
50%
|
2
33.3%
|
5
55.6%
|
4
66.7%
|
2
22.2%
|
5
83.3%
|
4
66.7%
|
5
71.4%
|
1
16.7%
|
5
55.6%
|
| Moderate |
0
0%
|
0
0%
|
2
22.2%
|
0
0%
|
0
0%
|
0
0%
|
1
16.7%
|
0
0%
|
4
66.7%
|
3
33.3%
|
| Severe |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
14.3%
|
0
0%
|
1
11.1%
|
| Life-Threatening |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Death |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Title | Incidence of Subjects Experiencing Dose-Limiting Toxicities (DLT) in Each Dose Cohort From Baseline Through End of Study Visit. |
|---|---|
| Description | DLT's were defined as an allergic reaction, acute bronchospasm or acute AEs of interest requiring (immediate) medical intervention. |
| Time Frame | 8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts |
Outcome Measure Data
| Analysis Population Description |
|---|
| All subjects who received either QR-010 or placebo. There were no Dose Limiting Toxicities (DLTs) reported in the SAD or MAD cohorts. |
| Arm/Group Title | QR-010 SAD 6.25 mg | QR-010 SAD 12.5 mg | QR-010 SAD 25 mg | QR-010 SAD 50 mg | Placebo SAD | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg | Placebo MAD |
|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation as a single dose Placebo: Normal Saline | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation three times weekly for four weeks. Placebo: Normal Saline |
| Measure Participants | 6 | 6 | 9 | 6 | 9 | 6 | 6 | 7 | 6 | 9 |
| Count of Participants [Participants] |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Title | Number of Subjects With Abnormalities Reported Regarding Laboratory Parameters, Vital Signs, ECG, Spirometry, and Physical Findings. |
|---|---|
| Description | Number of subjects experiencing at least one abnormality for the categories laboratory parameters, vital signs, ECG, spirometry and physical findings that were reported as treatment emergent adverse event with a relationship to study drug as either possibly, probably or definitely. |
| Time Frame | 8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts |
Outcome Measure Data
| Analysis Population Description |
|---|
| All subjects who received either QR-010 or placebo. |
| Arm/Group Title | QR-010 SAD 6.25 mg | QR-010 SAD 12.5 mg | QR-010 SAD 25 mg | QR-010 SAD 50 mg | Placebo SAD | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg | Placebo MAD |
|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation as a single dose Placebo: Normal Saline | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation three times weekly for four weeks. Placebo: Normal Saline |
| Measure Participants | 6 | 6 | 9 | 6 | 9 | 6 | 6 | 7 | 6 | 9 |
| laboratory parameters |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
1
14.3%
|
0
0%
|
3
33.3%
|
| vital signs |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| ECG |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Spirometry |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
0
0%
|
2
33.3%
|
1
11.1%
|
| physical findings |
2
33.3%
|
2
33.3%
|
2
22.2%
|
3
50%
|
0
0%
|
3
50%
|
4
66.7%
|
1
14.3%
|
1
16.7%
|
4
44.4%
|
| Title | Maximum Serum Concentration |
|---|---|
| Description | Cmax: QR-010 maximum serum concentrations |
| Time Frame | 8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts |
Outcome Measure Data
| Analysis Population Description |
|---|
| Study population included all subjects treated either with QR-010 or placebo. Quantifiable serum concentrations are only available for the 50mg SAD and 50 mg MAD cohorts. |
| Arm/Group Title | QR-010 SAD 6.25 mg | QR-010 SAD 12.5 mg | QR-010 SAD 25 mg | QR-010 SAD 50 mg | Placebo SAD | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg | Placebo MAD |
|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation as a single dose Placebo: Normal Saline | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation three times weekly for four weeks. Placebo: Normal Saline |
| Measure Participants | 0 | 0 | 0 | 4 | 0 | 0 | 0 | 0 | 6 | 0 |
| Dose 1 |
2.9
(1.2)
|
4.53
(3.38)
|
||||||||
| Week 4, Dose 12 |
NA
(NA)
|
3.63
(2.73)
|
| Title | Time to Maximum Serum Concentration |
|---|---|
| Description | Tmax: Time to Cmax of QR-010 serum concentrations. |
| Time Frame | 8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts |
Outcome Measure Data
| Analysis Population Description |
|---|
| Population included all subjects treated with either QR-010 or placebo. Quantifiable serum concentrations are only available for the 50mg SAD and MAD cohorts. |
| Arm/Group Title | QR-010 SAD 6.25 mg | QR-010 SAD 12.5 mg | QR-010 SAD 25 mg | QR-010 SAD 50 mg | Placebo SAD | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg | Placebo MAD |
|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation as a single dose Placebo: Normal Saline | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation three times weekly for four weeks. Placebo: Normal Saline |
| Measure Participants | 0 | 0 | 0 | 4 | 0 | 0 | 0 | 0 | 6 | 0 |
| Dose 1 |
0.6
|
0.5
|
||||||||
| Week 4, Dose 12 |
NA
|
1.0
|
| Title | Terminal Half-life (T1/2) |
|---|---|
| Description | The terminal elimination half-life will be estimated by non-linear regression analysis of the terminal elimination slope |
| Time Frame | 8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts |
Outcome Measure Data
| Analysis Population Description |
|---|
| The terminal half-life is not reported because the %AUC (Area Under the Curve) extrapolation was too large. |
| Arm/Group Title | QR-010 SAD 6.25 mg | QR-010 SAD 12.5 mg | QR-010 SAD 25 mg | QR-010 SAD 50 mg | Placebo SAD | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg | Placebo MAD |
|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation as a single dose Placebo: Normal Saline | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation three times weekly for four weeks. Placebo: Normal Saline |
| Measure Participants | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Title | Area Under the Curve to Final Sample [AUC(0-last)] |
|---|---|
| Description | Area under the curve to the final sample with a concentration greater than lower limit of quantification (LLQ) will be calculated using the linear trapezoidal method |
| Time Frame | 8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts |
Outcome Measure Data
| Analysis Population Description |
|---|
| Quantifiable serum concentrations are only available for the 50mg SAD and MAD cohort. For the PK parameters of the SAD 6.25, 12.5 and 25mg cohorts, no quantifiable serum concentrations could be measured. For the 6.25, 12.5 and 25mg MAD cohorts, no PK profiling was performed due to the large number of samples below the limit of detection. |
| Arm/Group Title | QR-010 SAD 6.25 mg | QR-010 SAD 12.5 mg | QR-010 SAD 25 mg | QR-010 SAD 50 mg | Placebo SAD | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg | Placebo MAD |
|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation as a single dose Placebo: Normal Saline | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation three times weekly for four weeks. Placebo: Normal Saline |
| Measure Participants | 0 | 0 | 0 | 4 | 0 | 0 | 0 | 0 | 6 | 0 |
| Dose 1 |
17.2
(8.2)
|
19.0
(15.6)
|
||||||||
| Week 4, Dose 12 |
NA
(NA)
|
17.0
(11.4)
|
| Title | Area Under the Curve to Infinity [AUC(0-∞)] |
|---|---|
| Description | AUC0-∞: Area under the curve to infinity will be calculated based on the last observed concentration Clast(obs) using formula: AUC0-∞=AUClast+Clast(obs)/λz |
| Time Frame | 8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Area Under the Curve to Infinity is not reported because the %AUC extrapolation was too large |
| Arm/Group Title | QR-010 SAD 6.25 mg | QR-010 SAD 12.5 mg | QR-010 SAD 25 mg | QR-010 SAD 50 mg | Placebo SAD | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg | Placebo MAD |
|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation as a single dose Placebo: Normal Saline | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation three times weekly for four weeks. Placebo: Normal Saline |
| Measure Participants | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Title | Serum Clearance (CL) |
|---|---|
| Description | CL: Serum clearance will be estimated using the formula: CL = Dose/AUC0-∞. |
| Time Frame | 8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts |
Outcome Measure Data
| Analysis Population Description |
|---|
| The Serum Clearance is not reported because the %AUC extrapolation was too large. |
| Arm/Group Title | QR-010 SAD 6.25 mg | QR-010 SAD 12.5 mg | QR-010 SAD 25 mg | QR-010 SAD 50 mg | Placebo SAD | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg | Placebo MAD |
|---|---|---|---|---|---|---|---|---|---|---|
| Arm/Group Description | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation as a single dose Placebo: Normal Saline | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation three times weekly for four weeks. Placebo: Normal Saline |
| Measure Participants | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
| Title | Adjusted Mean Change From Baseline in CFQ-R RSS |
|---|---|
| Description | Patient Reported Outcome measure Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Score (CFQ-R RSS). A higher score represents a better outcome. A minimal clinically important difference (MCID) in the respiratory domain (CFQ-R RSS) has been established in stable populations as 4.0 points, and a maximum score is 100 points. Mean values reported refer to ''adjusted mean change from baseline'' values. |
| Time Frame | Day 15, Day 33, Day 54 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All subjects treated with either QR-010 or placebo in the Multiple Ascending Dose cohorts that received at least 10 out of 12 doses. For 1 subject in the placebo group no data were available at Day 54. "Mean" in this table refers to "Adjusted Mean". |
| Arm/Group Title | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg | Placebo MAD |
|---|---|---|---|---|---|
| Arm/Group Description | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation three times weekly for four weeks. Placebo: Normal Saline |
| Measure Participants | 6 | 6 | 6 | 5 | 8 |
| Day 15 |
-4.13
(4.10)
|
8.95
(4.12)
|
7.76
(4.15)
|
-0.80
(4.51)
|
-5.09
(3.59)
|
| Day 33 |
6.43
(4.92)
|
12.65
(4.93)
|
7.76
(4.96)
|
-3.02
(5.40)
|
-6.48
(4.29)
|
| Day 54 |
-10.24
(6.56)
|
0.61
(6.57)
|
5.91
(6.59)
|
-4.13
(7.20)
|
-10.31
(5.87)
|
| Title | Adjusted Mean Change From Baseline in CFQ-R RSS as Compared to Placebo |
|---|---|
| Description | Patient Reported Outcome measure Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Score (CFQ-R RSS). A higher score represents a better outcome. A minimal clinically important difference (MCID) in the respiratory domain (CFQ-R RSS) has been established in stable populations as 4.0 points, and a maximum score is 100 points. Mean values reported refer to ''adjusted mean change from baseline'' values. |
| Time Frame | Day 15, Day 33, Day 54 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All subjects treated with either QR-010 or placebo in the Multiple Ascending Dose cohorts that received at least 10 out of 12 doses. |
| Arm/Group Title | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg |
|---|---|---|---|---|
| Arm/Group Description | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton |
| Measure Participants | 6 | 6 | 6 | 5 |
| Day 15 |
0.96
(5.46)
|
14.03
(5.49)
|
12.85
(5.55)
|
4.29
(5.73)
|
| Day 33 |
12.91
(6.53)
|
19.13
(6.56)
|
14.24
(6.60)
|
3.46
(6.87)
|
| Day 54 |
0.07
(8.81)
|
10.92
(8.83)
|
16.22
(8.87)
|
6.18
(9.26)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | QR-010 SAD 6.25 mg |
|---|---|---|
| Comments | A mixed-model analysis was performed with repeated time measures on the change from baseline CFQ-R RSS as outcome variable and including treatment, baseline CFQ-R RSS value, time and interaction between time and treatment as covariates. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0592 |
| Comments | p-values are presented for Day 33. | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference vs placebo |
| Estimated Value | 12.91 | |
| Confidence Interval |
(2-Sided) 95% -0.54 to 26.35 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 6.53 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | QR-010 SAD 12.5 mg |
|---|---|---|
| Comments | A mixed-model analysis was performed with repeated time measures on the change from baseline CFQ-R RSS as outcome variable and including treatment, baseline CFQ-R RSS value, time and interaction between time and treatment as covariates. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0074 |
| Comments | p-values are presented for Day 33 | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | difference vs placebo |
| Estimated Value | 19.13 | |
| Confidence Interval |
(2-Sided) 95% 5.62 to 32.64 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 6.56 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | QR-010 SAD 25 mg |
|---|---|---|
| Comments | A mixed-model analysis was performed with repeated time measures on the change from baseline CFQ-R RSS as outcome variable and including treatment, baseline CFQ-R RSS value, time and interaction between time and treatment as covariates. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0408 |
| Comments | p-values are presented for Day 33 | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | difference vs placebo |
| Estimated Value | 14.24 | |
| Confidence Interval |
(2-Sided) 95% 0.64 to 27.83 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 6.60 |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | QR-010 SAD 50 mg |
|---|---|---|
| Comments | A mixed-model analysis was performed with repeated time measures on the change from baseline CFQ-R RSS as outcome variable and including treatment, baseline CFQ-R RSS value, time and interaction between time and treatment as covariates. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.6193 |
| Comments | p-values are presented for Day 33 | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | difference vs placebo |
| Estimated Value | 3.46 | |
| Confidence Interval |
(2-Sided) 95% -10.69 to 17.60 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 6.87 |
|
| Estimation Comments | ||
| Title | Adjusted Mean Change From Baseline in CFQ-R RSS (Subgroup ppFEV1 <90% at Baseline) |
|---|---|
| Description | Patient Reported Outcome measure Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Score (CFQ-R RSS). A higher score represents a better outcome. A minimal clinically important difference (MCID) in the respiratory domain (CFQ-R RSS) has been established in stable populations as 4.0 points, and a maximum score is 100 points. Mean values reported refer to ''adjusted mean change from baseline'' values. |
| Time Frame | Day 15, Day 33, Day 54 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Subjects treated with either QR-010 or placebo in the Multiple Ascending Dose cohorts that received at least 10 out of 12 doses, with ppFEV1 <90% at baseline. For 1 subject in the placebo group no data were available at Day 54. "Mean" in this table refers to "Adjusted Mean". |
| Arm/Group Title | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg | Placebo MAD |
|---|---|---|---|---|---|
| Arm/Group Description | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation three times weekly for four weeks. Placebo: Normal Saline |
| Measure Participants | 3 | 4 | 5 | 4 | 4 |
| Day 15 |
-3.37
(5.51)
|
8.64
(4.87)
|
9.56
(4.28)
|
-0.87
(4.79)
|
-4.77
(4.82)
|
| Day 33 |
11.45
(7.36)
|
15.58
(6.44)
|
8.44
(5.71)
|
-0.87
(6.38)
|
-11.72
(6.41)
|
| Day 54 |
-3.37
(6.36)
|
5.86
(5.59)
|
7.33
(4.94)
|
-3.65
(5.52)
|
-6.49
(6.33)
|
| Title | Adjusted Mean Change From Baseline in CFQ-R RSS as Compared to Placebo (Subgroup ppFEV1 <90% at Baseline) |
|---|---|
| Description | Patient Reported Outcome measure Cystic Fibrosis Questionnaire-Revised Respiratory Symptom Score (CFQ-R RSS). A higher score represents a better outcome. A minimal clinically important difference (MCID) in the respiratory domain (CFQ-R RSS) has been established in stable populations as 4.0 points, and a maximum score is 100 points. Mean values reported refer to ''difference vs placebo in adjusted mean change from baseline'' values. |
| Time Frame | Day 15, Day 33, Day 54 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All subjects treated with either QR-010 or placebo in the Multiple Ascending Dose cohorts that received at least 10 out of 12 doses, with ppFEV1 <90% at Baseline. |
| Arm/Group Title | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg |
|---|---|---|---|---|
| Arm/Group Description | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton |
| Measure Participants | 3 | 4 | 5 | 4 |
| Day 15 |
1.41
(7.29)
|
13.41
(6.95)
|
14.33
(6.49)
|
3.90
(6.74)
|
| Day 33 |
23.17
(9.73)
|
27.30
(9.17)
|
20.16
(8.62)
|
10.84
(9.01)
|
| Day 54 |
3.12
(8.93)
|
12.35
(8.58)
|
13.82
(8.08)
|
2.84
(8.33)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | QR-010 SAD 6.25 mg |
|---|---|---|
| Comments | A mixed-model analysis was performed with repeated time measures on the change from baseline CFQ-R RSS as outcome variable and including treatment, baseline CFQ-R RSS value, time and interaction between time and treatment as covariates. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0321 |
| Comments | p-values are presented for Day 33. | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference vs placebo |
| Estimated Value | 23.17 | |
| Confidence Interval |
(2-Sided) 95% 2.29 to 44.04 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 9.73 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | QR-010 SAD 12.5 mg |
|---|---|---|
| Comments | A mixed-model analysis was performed with repeated time measures on the change from baseline CFQ-R RSS as outcome variable and including treatment, baseline CFQ-R RSS value, time and interaction between time and treatment as covariates. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0100 |
| Comments | p-values are presented for Day 33. | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference vs placebo |
| Estimated Value | 27.30 | |
| Confidence Interval |
(2-Sided) 95% 7.64 to 46.96 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 9.17 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | QR-010 SAD 25 mg |
|---|---|---|
| Comments | A mixed-model analysis was performed with repeated time measures on the change from baseline CFQ-R RSS as outcome variable and including treatment, baseline CFQ-R RSS value, time and interaction between time and treatment as covariates. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0346 |
| Comments | p-values are presented for Day 33. | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference vs placebo |
| Estimated Value | 20.16 | |
| Confidence Interval |
(2-Sided) 95% 1.68 to 38.64 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 8.62 |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | QR-010 SAD 50 mg |
|---|---|---|
| Comments | A mixed-model analysis was performed with repeated time measures on the change from baseline CFQ-R RSS as outcome variable and including treatment, baseline CFQ-R RSS value, time and interaction between time and treatment as covariates. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.2485 |
| Comments | p-values are presented for Day 33. | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference vs placebo |
| Estimated Value | 10.84 | |
| Confidence Interval |
(2-Sided) 95% -8.47 to 30.16 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 9.01 |
|
| Estimation Comments | ||
| Title | Adjusted Mean Change From Baseline in ppFEV1 |
|---|---|
| Description | Exploratory efficacy parameter, as measured by spirometry, and expressed in percent predicted FEV1 (ppFEV1). Mean values reported refer to ''adjusted mean change from baseline'' values. |
| Time Frame | Day 15, Day 33, Day 54 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All subjects treated with either QR-010 or placebo in the Multiple Ascending Dose cohorts that received at least 10 out of 12 doses. |
| Arm/Group Title | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg | Placebo MAD |
|---|---|---|---|---|---|
| Arm/Group Description | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation three times weekly for four weeks. Placebo: Normal Saline |
| Measure Participants | 6 | 6 | 6 | 5 | 8 |
| (pre-dose) Day 15 |
0.06
(1.96)
|
2.50
(1.96)
|
-4.03
(1.96)
|
-1.85
(2.14)
|
-0.83
(1.70)
|
| (pre-dose) Day 26 |
0.46
(2.64)
|
3.22
(2.64)
|
-0.98
(2.64)
|
-1.39
(2.89)
|
-0.80
(2.28)
|
| Day 33 |
1.54
(2.40)
|
0.05
(2.40)
|
-2.17
(2.40)
|
-3.21
(2.63)
|
-2.70
(2.08)
|
| Day 54 |
1.68
(2.88)
|
-1.63
(2.88)
|
0.61
(2.88)
|
-2.43
(3.15)
|
-2.58
(2.49)
|
| Title | Adjusted Mean Change From Baseline in ppFEV1 as Compared to Placebo |
|---|---|
| Description | Exploratory efficacy parameter, as measured by spirometry, and expresssed in percent predicted FEV1 (ppFEV1). Mean values reported refer to''difference vs placebo in adjusted mean change from baseline'' values. |
| Time Frame | Day 15, Day 33, Day 54 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All subjects treated with either QR-010 or placebo in the Multiple Ascending Dose cohorts that received at least 10 out of 12 doses. |
| Arm/Group Title | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg |
|---|---|---|---|---|
| Arm/Group Description | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton |
| Measure Participants | 6 | 6 | 6 | 5 |
| Day 15 |
0.89
(2.59)
|
3.32
(2.59)
|
-3.20
(2.59)
|
-1.02
(2.73)
|
| Day 26 |
1.26
(3.49)
|
4.02
(3.49)
|
-0.17
(3.49)
|
-0.59
(3.68)
|
| Day 33 |
4.24
(3.18)
|
2.75
(3.18)
|
0.53
(3.18)
|
-0.51
(3.35)
|
| Day 54 |
4.26
(3.81)
|
0.96
(3.80)
|
3.20
(3.81)
|
0.15
(4.01)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | QR-010 SAD 6.25 mg |
|---|---|---|
| Comments | A mixed-model analysis was performed with repeated time measures on the change from baseline ppFEV1 as outcome variable and including treatment, baseline ppFEV1 value, time and interaction between time and treatment as covariate | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.1938 |
| Comments | P-values are presented for Day 33 | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | difference vs placebo |
| Estimated Value | 4.24 | |
| Confidence Interval |
(2-Sided) 95% -2.30 to 10.79 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 3.18 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | QR-010 SAD 12.5 mg |
|---|---|---|
| Comments | A mixed-model analysis was performed with repeated time measures on the change from baseline ppFEV1 as outcome variable and including treatment, baseline ppFEV1 value, time and interaction between time and treatment as covariates. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.3943 |
| Comments | P-values are presented for Day 33 | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | difference vs placebo |
| Estimated Value | 2.75 | |
| Confidence Interval |
(2-Sided) 95% -3.79 to 9.29 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 3.18 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | QR-010 SAD 25 mg |
|---|---|---|
| Comments | A mixed-model analysis was performed with repeated time measures on the change from baseline ppFEV1 as outcome variable and including treatment, baseline ppFEV1 value, time and interaction between time and treatment as covariates. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.8688 |
| Comments | P-values are presented for Day 33 | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | difference vs placebo |
| Estimated Value | 0.53 | |
| Confidence Interval |
(2-Sided) 95% -6.01 to 7.07 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 3.18 |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | QR-010 SAD 50 mg |
|---|---|---|
| Comments | A mixed-model analysis was performed with repeated time measures on the change from baseline ppFEV1 as outcome variable and including treatment, baseline ppFEV1 value, time and interaction between time and treatment as covariates. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.8813 |
| Comments | P-values are presented for Day 33 | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | difference vs placebo |
| Estimated Value | -0.51 | |
| Confidence Interval |
(2-Sided) 95% -7.41 to 6.39 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 3.35 |
|
| Estimation Comments | ||
| Title | Adjusted Mean Change From Baseline in ppFEV1 (Subgroup ppFEV1 <90% at Baseline) |
|---|---|
| Description | Exploratory efficacy parameter, as measured by spirometry, and expresssed in percent predicted FEV1. Mean values reported refer to ''adjusted mean change from baseline'' values. |
| Time Frame | Day 15, Day 33, Day 54 |
Outcome Measure Data
| Analysis Population Description |
|---|
| All subjects treated with either QR-010 or placebo in the Multiple Ascending Dose cohorts that received at least 10 out of 12 doses, with ppFEV1 <90% at Baseline.. |
| Arm/Group Title | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg | Placebo MAD |
|---|---|---|---|---|---|
| Arm/Group Description | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation three times weekly for four weeks. Placebo: Normal Saline |
| Measure Participants | 3 | 4 | 5 | 4 | 4 |
| Day 15 |
-0.29
(2.22)
|
4.54
(1.92)
|
-3.45
(1.71)
|
-1.01
(1.91)
|
-3.40
(1.95)
|
| Day 26 |
4.21
(4.05)
|
7.15
(3.51)
|
0.89
(3.13)
|
-0.10
(3.50)
|
-3.76
(3.52)
|
| Day 33 |
6.01
(3.16)
|
3.81
(2.74)
|
-0.68
(2.44)
|
-0.97
(2.73)
|
-4.18
(2.76)
|
| Title | Adjusted Mean Change From Baseline in ppFEV1 as Compared to Placebo (Subgroup ppFEV1 <90% at Baseline) |
|---|---|
| Description | Exploratory efficacy parameter, as measured by spirometry, and expresssed in percent predicted FEV1. Mean values reported refer to ''difference vs placebo in adjusted mean change from baseline'' values. |
| Time Frame | Day 15, Day 33, Day 54 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Subjects treated with either QR-010 or placebo in the Multiple Ascending Dose cohorts that received at least 10 out of 12 doses, with ppFEV1 <90% at Baseline. |
| Arm/Group Title | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg |
|---|---|---|---|---|
| Arm/Group Description | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton |
| Measure Participants | 3 | 4 | 5 | 4 |
| Day 15 |
3.11
(2.99)
|
7.93
(2.76)
|
-0.05
(2.59)
|
2.38
(2.74)
|
| Day 26 |
7.97
(5.39)
|
10.90
(4.98)
|
4.65
(4.71)
|
3.65
(4.97)
|
| Day 33 |
10.19
(4.22)
|
7.99
(3.91)
|
3.50
(3.69)
|
3.21
(3.89)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | QR-010 SAD 6.25 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0301 |
| Comments | P-values are presented for Day 33 | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference vs placebo |
| Estimated Value | 10.19 | |
| Confidence Interval |
(2-Sided) 95% 1.13 to 19.25 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 4.22 |
|
| Estimation Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | QR-010 SAD 12.5 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0601 |
| Comments | P-values are presented for Day 33 | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference vs placebo |
| Estimated Value | 7.99 | |
| Confidence Interval |
(2-Sided) 95% -0.39 to 16.37 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 3.91 |
|
| Estimation Comments | ||
Statistical Analysis 3
| Statistical Analysis Overview | Comparison Group Selection | QR-010 SAD 25 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.3580 |
| Comments | P-values are presented for Day 33 | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference vs placebo |
| Estimated Value | 3.50 | |
| Confidence Interval |
(2-Sided) 95% -4.40 to 11.41 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 3.69 |
|
| Estimation Comments | ||
Statistical Analysis 4
| Statistical Analysis Overview | Comparison Group Selection | QR-010 SAD 50 mg |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4224 |
| Comments | P-values are presented for Day 33 | |
| Method | Mixed Models Analysis | |
| Comments | ||
| Method of Estimation | Estimation Parameter | Difference vs placebo |
| Estimated Value | 3.21 | |
| Confidence Interval |
(2-Sided) 95% -5.13 to 11.55 |
|
| Parameter Dispersion |
Type: Standard Error of the Mean Value: 3.89 |
|
| Estimation Comments | ||
Adverse Events
| Time Frame | For the SAD cohorts, from randomization up to Day 8 after dose administration. For the MAD cohorts, from randomization for at least 30 days after the last administration of the study treatment. | |||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||||||||||||||||
| Arm/Group Title | QR-010 SAD 6.25 mg | QR-010 SAD 12.5 mg | QR-010 SAD 25 mg | QR-010 SAD 50 mg | Placebo SAD | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg | Placebo MAD | ||||||||||
| Arm/Group Description | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation as a single dose QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation as a single dose Placebo: Normal Saline | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | QR-010 administered via inhalation three times weekly for four weeks. QR-010: Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton | Placebo (normal saline) administered via inhalation three times weekly for four weeks. Placebo: Normal Saline | ||||||||||
All Cause Mortality |
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| QR-010 SAD 6.25 mg | QR-010 SAD 12.5 mg | QR-010 SAD 25 mg | QR-010 SAD 50 mg | Placebo SAD | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg | Placebo MAD | |||||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/9 (0%) | ||||||||||
Serious Adverse Events |
||||||||||||||||||||
| QR-010 SAD 6.25 mg | QR-010 SAD 12.5 mg | QR-010 SAD 25 mg | QR-010 SAD 50 mg | Placebo SAD | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg | Placebo MAD | |||||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 0/6 (0%) | 0/7 (0%) | 1/6 (16.7%) | 1/9 (11.1%) | ||||||||||
| Gastrointestinal disorders | ||||||||||||||||||||
| Abdominal Pain | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/9 (0%) | 0 | 0/6 (0%) | 0 | 0/9 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/7 (0%) | 0 | 0/6 (0%) | 0 | 1/9 (11.1%) | 1 |
| Infections and infestations | ||||||||||||||||||||
| Respiratory Tract Infection | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/9 (0%) | 0 | 0/6 (0%) | 0 | 0/9 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/9 (0%) | 0 |
| Renal and urinary disorders | ||||||||||||||||||||
| Calculus Urinary | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/9 (0%) | 0 | 0/6 (0%) | 0 | 0/9 (0%) | 0 | 0/6 (0%) | 0 | 0/6 (0%) | 0 | 0/7 (0%) | 0 | 1/6 (16.7%) | 1 | 0/9 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
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| QR-010 SAD 6.25 mg | QR-010 SAD 12.5 mg | QR-010 SAD 25 mg | QR-010 SAD 50 mg | Placebo SAD | QR-010 MAD 6.25 mg | QR-010 MAD 12.5 mg | QR-010 MAD 25 mg | QR-010 MAD 50 mg | Placebo MAD | |||||||||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 3/6 (50%) | 2/6 (33.3%) | 7/9 (77.8%) | 4/6 (66.7%) | 2/9 (22.2%) | 5/6 (83.3%) | 5/6 (83.3%) | 6/7 (85.7%) | 5/6 (83.3%) | 9/9 (100%) | ||||||||||
| Gastrointestinal disorders | ||||||||||||||||||||
| Dry Mouth | 2/6 (33.3%) | 0/6 (0%) | 1/9 (11.1%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/9 (0%) | ||||||||||
| Diarrhoea | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 0/9 (0%) | 1/6 (16.7%) | 0/6 (0%) | 1/7 (14.3%) | 0/6 (0%) | 0/9 (0%) | ||||||||||
| Abdominal pain upper | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/6 (0%) | 0/6 (0%) | 0/7 (0%) | 1/6 (16.7%) | 1/9 (11.1%) | ||||||||||
| General disorders | ||||||||||||||||||||
| Fatigue | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 0/9 (0%) | 2/6 (33.3%) | 1/6 (16.7%) | 1/7 (14.3%) | 0/6 (0%) | 0/9 (0%) | ||||||||||
| Pyrexia | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 1/6 (16.7%) | 2/7 (28.6%) | 0/6 (0%) | 1/9 (11.1%) | ||||||||||
| Chest pain | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 1/6 (16.7%) | 0/7 (0%) | 0/6 (0%) | 1/9 (11.1%) | ||||||||||
| Chest discomfort | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/6 (0%) | 0/9 (0%) | 1/6 (16.7%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 1/9 (11.1%) | ||||||||||
| Infections and infestations | ||||||||||||||||||||
| Oral candidiasis | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 1/6 (16.7%) | 1/7 (14.3%) | 0/6 (0%) | 0/9 (0%) | ||||||||||
| Respiratory Tract Infection | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 0/6 (0%) | 0/7 (0%) | 2/6 (33.3%) | 0/9 (0%) | ||||||||||
| Rhinitis | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 2/6 (33.3%) | 0/7 (0%) | 0/6 (0%) | 0/9 (0%) | ||||||||||
| Injury, poisoning and procedural complications | ||||||||||||||||||||
| Sunburn | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/6 (0%) | 0/9 (0%) | 1/6 (16.7%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/9 (0%) | ||||||||||
| Investigations | ||||||||||||||||||||
| Forced expiratory volume decreased | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 0/6 (0%) | 0/7 (0%) | 2/6 (33.3%) | 2/9 (22.2%) | ||||||||||
| Metabolism and nutrition disorders | ||||||||||||||||||||
| Hyperglycaemia | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/9 (0%) | ||||||||||
| Musculoskeletal and connective tissue disorders | ||||||||||||||||||||
| Arthralgia | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 1/6 (16.7%) | 1/7 (14.3%) | 0/6 (0%) | 1/9 (11.1%) | ||||||||||
| Nervous system disorders | ||||||||||||||||||||
| Headache | 1/6 (16.7%) | 1/6 (16.7%) | 2/9 (22.2%) | 1/6 (16.7%) | 1/9 (11.1%) | 0/6 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/9 (0%) | ||||||||||
| Dizziness | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 2/6 (33.3%) | 0/9 (0%) | 0/6 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/9 (0%) | ||||||||||
| Psychiatric disorders | ||||||||||||||||||||
| Agitation | 0/6 (0%) | 1/6 (16.7%) | 0/9 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/9 (0%) | ||||||||||
| Respiratory, thoracic and mediastinal disorders | ||||||||||||||||||||
| Respiratory tract congestion | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 2/6 (33.3%) | 0/9 (0%) | 0/6 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/9 (0%) | ||||||||||
| Sputum increased | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 0/9 (0%) | 2/6 (33.3%) | 1/6 (16.7%) | 1/7 (14.3%) | 0/6 (0%) | 3/9 (33.3%) | ||||||||||
| Nasal congestion | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 0/9 (0%) | 2/6 (33.3%) | 0/6 (0%) | 0/7 (0%) | 1/6 (16.7%) | 1/9 (11.1%) | ||||||||||
| Oropharyngeal pain | 0/6 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 0/9 (0%) | 1/6 (16.7%) | 0/6 (0%) | 1/7 (14.3%) | 0/6 (0%) | 0/9 (0%) | ||||||||||
| Cough | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 1/6 (16.7%) | 0/9 (0%) | 3/6 (50%) | 1/6 (16.7%) | 0/7 (0%) | 2/6 (33.3%) | 2/9 (22.2%) | ||||||||||
| Wheezing | 0/6 (0%) | 0/6 (0%) | 1/9 (11.1%) | 0/6 (0%) | 0/9 (0%) | 3/6 (50%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/9 (0%) | ||||||||||
| Skin and subcutaneous tissue disorders | ||||||||||||||||||||
| Pruritus generalised | 0/6 (0%) | 1/6 (16.7%) | 0/9 (0%) | 0/6 (0%) | 0/9 (0%) | 0/6 (0%) | 0/6 (0%) | 0/7 (0%) | 0/6 (0%) | 0/9 (0%) | ||||||||||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Investigators are restricted from disclosure or results until after multicenter publication or 12 months after the completion of the Study at all participating research centers. Sponsor can review results communication prior to public release and can embargo communications regarding trial results for a period that is more than 45 days (varying per site). Sponsor may request redaction of confidential information.
Results Point of Contact
| Name/Title | Medical Monitor |
|---|---|
| Organization | ProQR Therapeutics |
| Phone | +31 6 20 183 437 |
| clinical@proqr.com |
Responsible Party:
ProQR Therapeutics
ClinicalTrials.gov Identifier:
NCT02532764
Other Study ID Numbers:
- PQ-010-001
First Posted:
Aug 26, 2015
Last Update Posted:
Feb 6, 2019
Last Verified:
Jan 1, 2019