Safety and Pharmacokinetic Study of N6022 in Subjects With Cystic Fibrosis Homozygous for the F508del-CFTR Mutation

Study Overview
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Brief Summary
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The purpose of this study is to investigate the safety, tolerability and pharmacokinetics of N6022, and to obtain descriptive information on the effect of N6022 on biomarkers of CFTR function and inflammation in adult cystic fibrosis subjects who are homozygous for the F508del-CFTR mutation.

Detailed Description
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This is a double-blind, randomized, placebo-controlled, multicenter, sequential dose-escalation study which will occur in two parts. All selection criteria, assessments and procedures described in this protocol will be applied to both parts. Up to 5 cohorts will be studied with a total of 67 patients at approximately 18 clinical sites in the United States.

Official Title
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A Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Dose Escalation Study of N6022 to Evaluate Safety and Pharmacokinetics in Subjects With Cystic Fibrosis Homozygous for the F508del-CFTR Mutation (SNO1)

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: N6022
* Drug: Normal saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Homozygous for F508del-CFTR gene Sweat chloride ≥ 60 mEq/L by quantitative pilocarpine iontophoresis Body weight ≥ 40 kg FEV1 ≥ 40% predicted Oxygen saturation ≥ 90% breathing ambient air Hematology and clinical chemistry of blood and urine results with no clinically significant abnormalities that would interfere with the study assessments Negative pregnancy test for women of child bearing potential Sexually active subjects of child bearing potential willing to follow contraception requirements Exclusion Criteria: Previous enrollment in another cohort for this study. Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment within 4 weeks of Study Day 1. Any change in chronic therapies for CF lung disease within 4 weeks of Study Day 1. Blood hemoglobin <10 g/dL at screening. Serum albumin <2.5 g/dL at screening. Abnormal liver function defined as ≥ 3 x upper limit of normal (ULN) in three or more of the following: AST, ALT, GGT, ALP, total bilirubin at screening. History of abnormal renal function (creatinine clearance < 50 mL/min using Cockcroft-Gault equation) within a year at screening. History, including the screening assessment, of ventricular tachycardia or other ventricular arrhythmias. History, including the screening assessment, of prolonged QT and/or QTcF interval (> 450 msec). History of solid organ or hematological transplantation. Intranasal medication changes within 14 days prior to Study Day 1 Required Use of continuous (24 hr/d) or nocturnal supplemental oxygen. Concomitant use of any inhibitors or inducers of CYP3A4.

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: N6022<br>Subjects randomized to study drug will receive N6022 by intravenous infusion once per day for 7 days | Drug: N6022<br>* Intravenous solution of N6022 in normal saline administered by infusion pump over 1-8 minutes depending on the dose<br>* Other names: GSNORi;|
| Placebo Comparator: Normal saline<br>Subjects randomized to placebo will receive normal saline administered intravenously using the same volume as the active drug group | Drug: Normal saline<br>* Intravenous solution of 0.9% (weight/volume) NaCl administered by infusion pump over 1-8 minutes depending on dose of active drug used in same cohort<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability | Assessments are based on numbers of subjects with abnormal clinical evaluations, abnormal laboratory assessments, and adverse events. | Over 7 treatment days and 7 days of follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) | FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. Hankinson standards were used to calculate percent predicted FEV1 (for age, sex, and height). | Change from baseline at Day 7 | 
| Change in Biomarkers of CFTR Function | Sweat chloride millequivalents/Liter (mEq/L) | Change from baseline at Day 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cystic Fibrosis, F508del-CFTR, N6022, S-Nitrosoglutathione