Safety and Pharmacokinetic Study of N6022 in Subjects With Cystic Fibrosis Homozygous for the F508del-CFTR Mutation (SNO-1)

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)

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.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: N6022; Drug: Normal saline

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama
  • Alaska
    • Anchorage, Alaska, United States, 99508
      • Providence Alaska Medical Center
  • California
    • Palo Alto, California, United States, 94304
      • Stanford University
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Health
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Children's Hospital
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Washington University
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital
    • Cleveland, Ohio, United States, 44106
      • Rainbow Babies and Children's Hospital - Case Medical Center
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: N6022; Subjects randomized to study drug will receive N6022 by intravenous infusion once per day for 7 days	Drug: N6022; Intravenous solution of N6022 in normal saline administered by infusion pump over 1-8 minutes depending on the dose; Other Names: GSNORi
PLACEBO_COMPARATOR: Normal saline; Subjects randomized to placebo will receive normal saline administered intravenously using the same volume as the active drug group	Drug: Normal saline; 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; Other Names: Placebo

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Nivalis Therapeutics, Inc.

Publications and helpful links

General Publications

• Southern KW, Murphy J, Sinha IP, Nevitt SJ. Corrector therapies (with or without potentiators) for people with cystic fibrosis with class II CFTR gene variants (most commonly F508del). Cochrane Database Syst Rev. 2020 Dec 17;12(12):CD010966. doi: 10.1002/14651858.CD010966.pub3.

Helpful Links

• Home page of Sponsor

Study record dates

Study Major Dates

• Study Start: February 1, 2014
• Primary Completion (ACTUAL): April 1, 2014
• Study Completion (ACTUAL): May 1, 2014

Study Registration Dates

• First Submitted: December 6, 2012
• First Submitted That Met QC Criteria: December 10, 2012
• First Posted (ESTIMATE): December 11, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): November 24, 2014
• Last Update Submitted That Met QC Criteria: November 21, 2014
• Last Verified: November 1, 2014

More Information

Terms related to this study

• Keywords: Cystic Fibrosis; F508del-CFTR; N6022; S-Nitrosoglutathione
• 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: N6022-1CF1-04