Dose Escalation Study of QR-010 in Homozygous ΔF508 Cystic Fibrosis Patients

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

A randomized, double-blind, placebo-controlled study of single and multiple ascending doses of QR-010 in adults homozygous for ΔF508 Cystic Fibrosis.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: Placebo; Drug: QR-010

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 Type: Interventional
• Enrollment (Actual): 70
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 01090
    • Universitair Ziekenhuis Brussel
  • Leuven, Belgium, 03000
    • University of Leuven
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N1
      • University of Calgary (Health Sciences Centre)
• Czechia
  • Prague, Czechia, 15006
    • Motol University Hospital
• Denmark
  • Copenhagen, Denmark, 02100
    • Cystic Fibrosis Center Rigshospitalet
• France
  • Nantes, France, 44300
    • HGRL Chu Nantes
  • Paris, France, 75743
    • Hôpital Necker- Enfants Malades
• Germany
  • Berlin, Germany, 13353
    • Charité Universitätsmedizin Berlin
  • Hannover, Germany, 30625
    • Medizinische Hochschule Hannover
  • Munich, Germany, 80336
    • Munich U. Hospital, Cystic Fibrosis Center for Adults
• Italy
  • Verona, Italy, 37134
    • Azienda Ospedaliera Universitaria Integrata di Verona
• Spain
  • Barcelona, Spain, 08035
    • Hospital Vall D'Hebron
• United Kingdom
  • London, United Kingdom, SW3 6NP
    • Royal Brompton Hospital
  • Southampton, United Kingdom, SO16 6YD
    • Southampton General Hospital
  • Northern Ireland
    • Belfast, Northern Ireland, United Kingdom, BT9 6AD
      • Celerion
• United States
  • California
    • Los Angeles, California, United States, 90033
      • University of Southern California USC - Keck School of Medicine
    • Palo Alto, California, United States, 940304
      • Stanford University
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center Research Institute
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110-1032
      • Washington University School of Medicine
  • Ohio
    • Columbus, Ohio, United States, 66160
      • Nationwide Children's Hospital
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Milton S. Hershey Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center
  • Washington
    • Seattle, Washington, United States, 98195-6522
      • University of Washington Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 56 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Subjects Experiencing Treatment Emergent Adverse Events From Baseline Through End of Study	Number of subjects experiencing at least one treatment emergent adverse events (TEAEs)	8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts
Severity of Treatment Emergent Adverse Events From Baseline Through End of Study	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.	8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts
Incidence of Subjects Experiencing Dose-Limiting Toxicities (DLT) in Each Dose Cohort From Baseline Through End of Study Visit.	DLT's were defined as an allergic reaction, acute bronchospasm or acute AEs of interest requiring (immediate) medical intervention.	8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Subjects With Abnormalities Reported Regarding Laboratory Parameters, Vital Signs, ECG, Spirometry, and Physical Findings.	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.	8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts
Maximum Serum Concentration	Cmax: QR-010 maximum serum concentrations	8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts
Time to Maximum Serum Concentration	Tmax: Time to Cmax of QR-010 serum concentrations.	8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts
Terminal Half-life (T1/2)	The terminal elimination half-life will be estimated by non-linear regression analysis of the terminal elimination slope	8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts
Area Under the Curve to Final Sample [AUC(0-last)]	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	8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts
Area Under the Curve to Infinity [AUC(0-∞)]	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	8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts
Serum Clearance (CL)	CL: Serum clearance will be estimated using the formula: CL = Dose/AUC0-∞.	8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adjusted Mean Change From Baseline in CFQ-R RSS	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.	Day 15, Day 33, Day 54
Adjusted Mean Change From Baseline in CFQ-R RSS as Compared to Placebo	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.	Day 15, Day 33, Day 54
Adjusted Mean Change From Baseline in CFQ-R RSS (Subgroup ppFEV1 <90% at Baseline)	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.	Day 15, Day 33, Day 54
Adjusted Mean Change From Baseline in CFQ-R RSS as Compared to Placebo (Subgroup ppFEV1 <90% at Baseline)	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.	Day 15, Day 33, Day 54
Adjusted Mean Change From Baseline in ppFEV1	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.	Day 15, Day 33, Day 54
Adjusted Mean Change From Baseline in ppFEV1 as Compared to Placebo	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.	Day 15, Day 33, Day 54
Adjusted Mean Change From Baseline in ppFEV1 (Subgroup ppFEV1 <90% at Baseline)	Exploratory efficacy parameter, as measured by spirometry, and expresssed in percent predicted FEV1. Mean values reported refer to ''adjusted mean change from baseline'' values.	Day 15, Day 33, Day 54
Adjusted Mean Change From Baseline in ppFEV1 as Compared to Placebo (Subgroup ppFEV1 <90% at Baseline)	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.	Day 15, Day 33, Day 54

Collaborators and Investigators

• Sponsor: ProQR Therapeutics
• Collaborators: European Commission
• Investigators: Principal Investigator: Stuart Elborn, MD, Trust and Queen's University Belfast

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: June 1, 2015
• Primary Completion (Actual): September 14, 2017
• Study Completion (Actual): September 14, 2017

Study Registration Dates

• First Submitted: August 13, 2015
• First Submitted That Met QC Criteria: August 21, 2015
• First Posted (Estimate): August 26, 2015

Study Record Updates

• Last Update Posted (Actual): February 6, 2019
• Last Update Submitted That Met QC Criteria: January 15, 2019
• Last Verified: January 1, 2019

More Information

Terms related to this study

• Keywords: cystic fibrosis; CFTR; CF; F508del; RNA therapies; antisense oligonucleotide; RNA therapy; ΔF508
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis
• Other Study ID Numbers: PQ-010-001