Cystic Fibrosis
Conditions
Keywords
Cystic Fibrosis, F508del-CFTR, N6022, S-Nitrosoglutathione
Brief summary
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
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.
Interventions
DRUGN6022
Intravenous solution of N6022 in normal saline administered by infusion pump over 1-8 minutes depending on the dose
DRUGNormal 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
Sponsors
Nivalis Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and Tolerability | Over 7 treatment days and 7 days of follow-up | Assessments are based on numbers of subjects with abnormal clinical evaluations, abnormal laboratory assessments, and adverse events. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) | Change from baseline at Day 7 | 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 in Biomarkers of CFTR Function | Change from baseline at Day 7 | Sweat chloride millequivalents/Liter (mEq/L) |
Countries
United States
Participant flow
Recruitment details
17 Clinical Investigator Sites enrolled 66 subjects. The first patient was screened on March 5, 2013 and the last patient was seen on April 10, 2014.
Pre-assignment details
There were 4 ascending dose cohorts starting at 5 mg and continuing with 10 mg, 20 mg and 40 mg. There was a fifth confirmatory cohort at the maximum tested dose, 40 mg. In Cohorts 1-4 approximately 9 subjects received N6022 and 3 received placebo. In the fifth cohort 11 subjects received N6022 and 7 subjects receive placebo
Participants by arm
| Arm | Count |
|---|---|
| Normal Saline Normal saline: IV solution of 0.9% (weight/volume) NaCl administered by infusion pump over 1-8 minutes | 19 |
| 5mg/N6022 N6022: Intravenous solution of N6022 in normal saline administered by infusion pump over 1-8 minutes once per day for 7 days | 10 |
| 10mg/N6022 N6022: Intravenous solution of N6022 in normal saline administered by infusion pump over 1-8 minutes once per day for 7 days | 9 |
| 20mg/N6022 N6022: Intravenous solution of N6022 in normal saline administered by infusion pump over 1-8 minutes once per day for 7 days | 9 |
| 40mg/N6022 N6022: Intravenous solution of N6022 in normal saline administered by infusion pump over 1-8 minutes once per day for 7 days | 19 |
| Total | 66 |
Baseline characteristics
| Characteristic | Normal Saline | Total | 40mg/N6022 | 20mg/N6022 | 10mg/N6022 | 5mg/N6022 |
|---|---|---|---|---|---|---|
| Age, Continuous | 29.0 years STANDARD_DEVIATION 7.27 | 28.9 years STANDARD_DEVIATION 7.93 | 28.4 years STANDARD_DEVIATION 8.46 | 28.6 years STANDARD_DEVIATION 10.3 | 32.3 years STANDARD_DEVIATION 7.84 | 26.9 years STANDARD_DEVIATION 6.33 |
| Body Mass Index (BMI) | 21.4 kg/^m2 STANDARD_DEVIATION 3.25 | 21.9 kg/^m2 STANDARD_DEVIATION 3.25 | 22.5 kg/^m2 STANDARD_DEVIATION 2.62 | 21.0 kg/^m2 STANDARD_DEVIATION 3.8 | 21.7 kg/^m2 STANDARD_DEVIATION 2.27 | 21.7 kg/^m2 STANDARD_DEVIATION 4.59 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 66 Participants | 19 Participants | 9 Participants | 9 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| FEV1 (L) | 2.7 L STANDARD_DEVIATION 0.85 | 2.5 L STANDARD_DEVIATION 0.97 | 2.8 L STANDARD_DEVIATION 1.12 | 2.1 L STANDARD_DEVIATION 0.66 | 2.2 L STANDARD_DEVIATION 0.91 | 2.6 L STANDARD_DEVIATION 0.88 |
| FEV1 Percent Predicted | 72.5 percent STANDARD_DEVIATION 23.7 | 70.1 percent STANDARD_DEVIATION 21.3 | 73.9 percent STANDARD_DEVIATION 21.9 | 63.2 percent STANDARD_DEVIATION 21.1 | 63.3 percent STANDARD_DEVIATION 17.5 | 70.7 percent STANDARD_DEVIATION 19.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 19 Participants | 66 Participants | 19 Participants | 9 Participants | 9 Participants | 10 Participants |
| Region of Enrollment United States | 19 participants | 66 participants | 19 participants | 9 participants | 9 participants | 10 participants |
| Sex: Female, Male Female | 10 Participants | 40 Participants | 11 Participants | 7 Participants | 6 Participants | 6 Participants |
| Sex: Female, Male Male | 9 Participants | 26 Participants | 8 Participants | 2 Participants | 3 Participants | 4 Participants |
| Sweat Chloride | 100.4 mEq/L STANDARD_DEVIATION 12.9 | 100.8 mEq/L STANDARD_DEVIATION 10.7 | 100.3 mEq/L STANDARD_DEVIATION 8.3 | 93.1 mEq/L STANDARD_DEVIATION 9.2 | 107.3 mEq/L STANDARD_DEVIATION 6.7 | 103.3 mEq/L STANDARD_DEVIATION 6.9 |
| Weight | 62.9 kg STANDARD_DEVIATION 11.5 | 61.0 kg STANDARD_DEVIATION 11.96 | 63.8 kg STANDARD_DEVIATION 12.53 | 56.3 kg STANDARD_DEVIATION 13.59 | 59.1 kg STANDARD_DEVIATION 9.06 | 61.8 kg STANDARD_DEVIATION 11.73 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 18 / 19 | 9 / 10 | 9 / 9 | 9 / 9 | 15 / 19 |
| serious Total, serious adverse events | 1 / 19 | 2 / 10 | 0 / 9 | 0 / 9 | 1 / 19 |
Outcome results
Primary
Safety and Tolerability
Assessments are based on numbers of subjects with abnormal clinical evaluations, abnormal laboratory assessments, and adverse events.
Time frame: Over 7 treatment days and 7 days of follow-up
Population: Treatment emergent adverse events by Grade 1 (mild) to 5 (fatal)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Normal Saline | Safety and Tolerability | Grade 3 (severe) | 1 participants |
| Normal Saline | Safety and Tolerability | Grade 1 (mild) | 11 participants |
| Normal Saline | Safety and Tolerability | Grade 4 (life threatening) | 0 participants |
| Normal Saline | Safety and Tolerability | Serious TEAE | 1 participants |
| Normal Saline | Safety and Tolerability | Grade 2 (moderate) | 6 participants |
| Normal Saline | Safety and Tolerability | Grade 5 (fatal) | 0 participants |
| 5mg/N6022 | Safety and Tolerability | Grade 1 (mild) | 4 participants |
| 5mg/N6022 | Safety and Tolerability | Grade 2 (moderate) | 3 participants |
| 5mg/N6022 | Safety and Tolerability | Grade 4 (life threatening) | 0 participants |
| 5mg/N6022 | Safety and Tolerability | Grade 5 (fatal) | 0 participants |
| 5mg/N6022 | Safety and Tolerability | Serious TEAE | 2 participants |
| 5mg/N6022 | Safety and Tolerability | Grade 3 (severe) | 2 participants |
| 10mg/N6022 | Safety and Tolerability | Grade 5 (fatal) | 0 participants |
| 10mg/N6022 | Safety and Tolerability | Serious TEAE | 0 participants |
| 10mg/N6022 | Safety and Tolerability | Grade 2 (moderate) | 3 participants |
| 10mg/N6022 | Safety and Tolerability | Grade 3 (severe) | 0 participants |
| 10mg/N6022 | Safety and Tolerability | Grade 1 (mild) | 6 participants |
| 10mg/N6022 | Safety and Tolerability | Grade 4 (life threatening) | 0 participants |
| 20mg/N6022 | Safety and Tolerability | Grade 5 (fatal) | 0 participants |
| 20mg/N6022 | Safety and Tolerability | Grade 4 (life threatening) | 0 participants |
| 20mg/N6022 | Safety and Tolerability | Grade 1 (mild) | 4 participants |
| 20mg/N6022 | Safety and Tolerability | Grade 2 (moderate) | 5 participants |
| 20mg/N6022 | Safety and Tolerability | Serious TEAE | 0 participants |
| 20mg/N6022 | Safety and Tolerability | Grade 3 (severe) | 0 participants |
| 40mg/N6022 | Safety and Tolerability | Serious TEAE | 1 participants |
| 40mg/N6022 | Safety and Tolerability | Grade 1 (mild) | 12 participants |
| 40mg/N6022 | Safety and Tolerability | Grade 2 (moderate) | 2 participants |
| 40mg/N6022 | Safety and Tolerability | Grade 3 (severe) | 1 participants |
| 40mg/N6022 | Safety and Tolerability | Grade 4 (life threatening) | 0 participants |
| 40mg/N6022 | Safety and Tolerability | Grade 5 (fatal) | 0 participants |
Secondary
Change in Biomarkers of CFTR Function
Sweat chloride millequivalents/Liter (mEq/L)
Time frame: Change from baseline at Day 7
Population: Change from baseline sweat chloride (mEq/L) to Study Day 14
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Saline | Change in Biomarkers of CFTR Function | -0.2 mEq/L | Standard Deviation 8.55 |
| 5mg/N6022 | Change in Biomarkers of CFTR Function | -2.3 mEq/L | Standard Deviation 8.12 |
| 10mg/N6022 | Change in Biomarkers of CFTR Function | -2.9 mEq/L | Standard Deviation 8.84 |
| 20mg/N6022 | Change in Biomarkers of CFTR Function | -0.1 mEq/L | Standard Deviation 11.25 |
| 40mg/N6022 | Change in Biomarkers of CFTR Function | 2.9 mEq/L | Standard Deviation 8.88 |
Secondary
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).
Time frame: Change from baseline at Day 7
Population: Change in Forced Expiratory Volume in 1 second (FEV1) from baseline to Study Day 7
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Normal Saline | Change in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) | 1.5 percentage | Standard Deviation 3.44 |
| 5mg/N6022 | Change in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) | -0.5 percentage | Standard Deviation 4.72 |
| 10mg/N6022 | Change in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) | -0.2 percentage | Standard Deviation 3.99 |
| 20mg/N6022 | Change in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) | -0.7 percentage | Standard Deviation 4.08 |
| 40mg/N6022 | Change in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1) | 0.5 percentage | Standard Deviation 3.04 |