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

Cystic Fibrosis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02532764
• Other study ID #: PQ-010-001
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: June 2015
• Est. completion date: September 14, 2017

Study information

• Verified date: January 2019
• Source: ProQR Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 70
• Est. completion date: September 14, 2017
• Est. primary completion date: September 14, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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 ?F508 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

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis

Intervention

Drug:
• QR-010
Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton
• Placebo
Normal Saline

Locations

Country	Name	City	State
Belgium	Universitair Ziekenhuis Brussel	Brussels
Belgium	University of Leuven	Leuven
Canada	University of Calgary (Health Sciences Centre)	Calgary	Alberta
Czechia	Motol University Hospital	Prague
Denmark	Cystic Fibrosis Center Rigshospitalet	Copenhagen
France	HGRL Chu Nantes	Nantes
France	Hopital Necker- Enfants Malades	Paris
Germany	Charité Universitätsmedizin Berlin	Berlin
Germany	Medizinische Hochschule Hannover	Hannover
Germany	Munich U. Hospital, Cystic Fibrosis Center for Adults	Munich
Italy	Azienda Ospedaliera Universitaria Integrata di Verona	Verona
Spain	Hospital Vall D'Hebron	Barcelona
United Kingdom	Celerion	Belfast	Northern Ireland
United Kingdom	Royal Brompton Hospital	London
United Kingdom	Southampton General Hospital	Southampton
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Medical University of South Carolina	Charleston	South Carolina
United States	Northwestern University	Chicago	Illinois
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania
United States	University of Kansas Medical Center Research Institute	Kansas City	Kansas
United States	University of Southern California USC - Keck School of Medicine	Los Angeles	California
United States	Stanford University	Palo Alto	California
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of Washington Medical Center	Seattle	Washington

Sponsors (2)

Lead Sponsor	Collaborator
ProQR Therapeutics	European Commission

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Czechia,  Denmark,  France,  Germany,  Italy,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Primary	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
Primary	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
Primary	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	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
Secondary	Maximum Serum Concentration	Cmax: QR-010 maximum serum concentrations	8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts
Secondary	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
Secondary	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
Secondary	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
Secondary	Area Under the Curve to Infinity [AUC(0-8)]	AUC0-8: Area under the curve to infinity will be calculated based on the last observed concentration Clast(obs) using formula: AUC0-8=AUClast+Clast(obs)/?z	8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts
Secondary	Serum Clearance (CL)	CL: Serum clearance will be estimated using the formula: CL = Dose/AUC0-8.	8 Days for Single-dose cohorts; 8 weeks for Multiple-dose cohorts