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

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

Detailed Description
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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.

Official Title
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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

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: QR-010
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of CF as defined by iontophoretic pilocarpine sweat chloride test (sweat chloride) of > 60 mmol/L 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: QR-010<br>QR-010 administered via inhalation either as a single dose or three times weekly for four weeks. | Drug: QR-010<br>* Single-stranded RNA antisense oligonucleotide in aqueous solution for oral inhalaton<br>|
| Placebo Comparator: Placebo<br>Placebo (normal saline) administered via inhalation either as a single dose or three times weekly for four weeks. | Drug: Placebo<br>* Normal Saline<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cystic fibrosis, ΔF508, RNA therapies, antisense oligonucleotide, CFTR, F508del, CF, RNA therapy