Healthy
Conditions
Keywords
N6022, GSNORi
Brief summary
This Phase 1 study will evaluate multiple doses across a range that has been found to be effective in mouse models of asthma and safe in one Phase 1 clinical trial. It is intended to provide evidence of the tolerability of multiple doses as well as provide information on the Pharmacokinetic (PK) and metabolism of N6022 in humans.
Detailed description
This is a double-blind, randomized, placebo-controlled, multiple ascending dose study, in at least three ascending cohorts. Twenty-four subjects will be enrolled initially in the first three cohorts, with up to 40 subjects to be enrolled overall if additional cohorts are required to reach the maximum tolerated dose (MTD). The cohorts will be enrolled in two groups of 4 each with approximately 7 days between groups to conduct safety monitoring committee review for approval to proceed to the second group in the cohort. Eight subjects will be enrolled per cohort, randomized 3:1 to N6022: placebo. Each subject will undergo screening (Day -28 to Day -2) and, if eligible, they will be instructed to begin a low-nitrate diet on Day -4. Subjects will return to the clinical site on Day -1, and eligibility will be reconfirmed. Eligible subjects will receive a dose of investigational medicinal product (\[IMP\], N6022 or placebo) by intravenous (IV) infusion on study Days 1 through 7 and will be followed for safety, PK, and PD until discharge on the morning of Day 8. Subjects will return to the clinic for a follow-up visit on Day 15 (± 1 day) and will be contacted via telephone on Day 28 (± 1 day) for the end-of-study safety follow-up visit. Participation of an individual subject may last approximately 56 days from the time of screening until the end-of-study follow-up visit. A Safety Monitoring Committee (SMC) will review the safety data in each cohort after the Day 15 Follow-up visit, before proceeding to the next ascending dose cohort, modifying the dose, repeating a dose, or stopping the study according to the stopping rules outlined in the protocol.
Interventions
DRUG5 mg/N6022
Intravenous formulation, given at doses of 5 mg once each day over 7 days.
DRUGPlacebo
Same administration procedures as active
DRUG10mg/N6022
Intravenous formulation given at doses of 10 mg once each day over 7 days.
DRUG20mg/N6022
Intravenous formulation given at doses of 20 mg once each day over 7 days.
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 45 Years
Healthy volunteers
Yes
Inclusion criteria
1. Subject is healthy, determined by pre-study medical evaluation (medical history, physical examination, vital signs, 12-lead ECG, and clinical laboratory evaluations 2. Subject is a non-smoker (or other nicotine user) as determined by history (no nicotine use over the past year) and a negative urine cotinine test at screening and Day 1. 3. Subject has a body weight \> 50 kg and BMI between 19.5 and 29.5 kg/m2, inclusive, at screening. 4. Subject has systolic BP \> 90 mmHg and diastolic BP \> 50 mmHg at screening or Day-1.
Exclusion criteria
1. Subject has clinically significant history or evidence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, endocrine, neurological, immunological, or psychiatric disorder(s) as determined by the investigator or designee. 2. Subject is a current alcohol abuser and/or has a history of illicit drug abuse within six months of entry. 3. Subject has donated blood (\> 500 mL) or blood products within 56 days prior to Day -1. 4. Subject has a history of bleeding disorders (i.e., severe hemorrhage, melena, rectal bleeding, nosebleeds, bruising, etc.).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety of Escalating Multiple Doses of N6022 in Healthy Subjects | Over 7 days | Safety variables (adverse events, vital signs, physical examination, telemetry, 12-lead ECG, infusion site reactions, O2 saturation, and clinical laboratory assessments) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pharmacokinetics of N6022 | Day 1, 24 hours | N6022 AUC0-tau measurements from Day 1 |
| Pharmacokinetics of N6022 Over 7 Days | Day 7, 24 hours | Analysis of N6022 AUC0-tau values from Study Day 7 |
| Pharmacokinetics of N6022 on Study Day 1 | Day 1, 24 hours | Analysis of N6022 Cmax values on Study Day 1 |
| Pharmacokinetics of N6022 Cmax Values on Study Day 7 | Day 7, 24 hours | Pharmacokinetic Analysis of N6022 Cmax values on Study Day 7 |
Countries
United States
Participant flow
Recruitment details
Recruitment occurred between 06April2011 and 09August2011. This study was done at a single Phase 1 site.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 N6022 - Active 5 mg | 7 |
| Cohort 2 N6022 - Active 10 mg | 6 |
| Cohort 3 N6022 - Active 20 mg | 6 |
| Placebo Non-Active | 6 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Cohort 2 | Cohort 3 | Cohort 1 | Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 6 Participants | 6 Participants | 7 Participants | 6 Participants | 25 Participants |
| Age, Continuous | 31 years | 35 years | 32 years | 35 years | 33 years |
| Region of Enrollment United States | 6 participants | 6 participants | 7 participants | 6 participants | 25 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 7 Participants | 6 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 7 | 2 / 6 | 4 / 6 | 5 / 6 |
| serious Total, serious adverse events | 0 / 7 | 0 / 6 | 0 / 6 | 0 / 6 |
Outcome results
Primary
Safety of Escalating Multiple Doses of N6022 in Healthy Subjects
Safety variables (adverse events, vital signs, physical examination, telemetry, 12-lead ECG, infusion site reactions, O2 saturation, and clinical laboratory assessments)
Time frame: Over 7 days
Population: Any subject that received any dose of N6022 or placebo.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Safety of Escalating Multiple Doses of N6022 in Healthy Subjects | Number of subjects on study | 7 participants |
| Cohort 1 | Safety of Escalating Multiple Doses of N6022 in Healthy Subjects | Treatment related AE | 0 participants |
| Cohort 1 | Safety of Escalating Multiple Doses of N6022 in Healthy Subjects | Early Termination | 1 participants |
| Cohort 2 | Safety of Escalating Multiple Doses of N6022 in Healthy Subjects | Number of subjects on study | 6 participants |
| Cohort 2 | Safety of Escalating Multiple Doses of N6022 in Healthy Subjects | Treatment related AE | 0 participants |
| Cohort 2 | Safety of Escalating Multiple Doses of N6022 in Healthy Subjects | Early Termination | 0 participants |
| Cohort 3 | Safety of Escalating Multiple Doses of N6022 in Healthy Subjects | Early Termination | 1 participants |
| Cohort 3 | Safety of Escalating Multiple Doses of N6022 in Healthy Subjects | Number of subjects on study | 6 participants |
| Cohort 3 | Safety of Escalating Multiple Doses of N6022 in Healthy Subjects | Treatment related AE | 1 participants |
| Placebo | Safety of Escalating Multiple Doses of N6022 in Healthy Subjects | Number of subjects on study | 6 participants |
| Placebo | Safety of Escalating Multiple Doses of N6022 in Healthy Subjects | Treatment related AE | 0 participants |
| Placebo | Safety of Escalating Multiple Doses of N6022 in Healthy Subjects | Early Termination | 0 participants |
Secondary
Pharmacokinetics of N6022
N6022 AUC0-tau measurements from Day 1
Time frame: Day 1, 24 hours
Population: Any subject that completed N6022 or placebo PK sampling
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Pharmacokinetics of N6022 | 138 h*ng/mL | Geometric Coefficient of Variation 13 |
| Cohort 2 | Pharmacokinetics of N6022 | 334 h*ng/mL | Geometric Coefficient of Variation 21.1 |
| Cohort 3 | Pharmacokinetics of N6022 | 669 h*ng/mL | Geometric Coefficient of Variation 16.9 |
| Placebo | Pharmacokinetics of N6022 | 0 h*ng/mL | Geometric Coefficient of Variation 0 |
Secondary
Pharmacokinetics of N6022 Cmax Values on Study Day 7
Pharmacokinetic Analysis of N6022 Cmax values on Study Day 7
Time frame: Day 7, 24 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Pharmacokinetics of N6022 Cmax Values on Study Day 7 | 287 ng/mL | Geometric Coefficient of Variation 89.8 |
| Cohort 2 | Pharmacokinetics of N6022 Cmax Values on Study Day 7 | 1110 ng/mL | Geometric Coefficient of Variation 34.1 |
| Cohort 3 | Pharmacokinetics of N6022 Cmax Values on Study Day 7 | 2320 ng/mL | Geometric Coefficient of Variation 13.5 |
| Placebo | Pharmacokinetics of N6022 Cmax Values on Study Day 7 | 0 ng/mL | Geometric Coefficient of Variation 0 |
Secondary
Pharmacokinetics of N6022 on Study Day 1
Analysis of N6022 Cmax values on Study Day 1
Time frame: Day 1, 24 hours
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Pharmacokinetics of N6022 on Study Day 1 | 465 ng/mL | Geometric Coefficient of Variation 69.8 |
| Cohort 2 | Pharmacokinetics of N6022 on Study Day 1 | 1270 ng/mL | Geometric Coefficient of Variation 95.6 |
| Cohort 3 | Pharmacokinetics of N6022 on Study Day 1 | 1400 ng/mL | Geometric Coefficient of Variation 86.2 |
| Placebo | Pharmacokinetics of N6022 on Study Day 1 | 0 ng/mL | Geometric Coefficient of Variation 0 |
Secondary
Pharmacokinetics of N6022 Over 7 Days
Analysis of N6022 AUC0-tau values from Study Day 7
Time frame: Day 7, 24 hours
Population: N6022 AUC0-tau values from Study Day 7
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | Pharmacokinetics of N6022 Over 7 Days | 149 h*ng/mL | Geometric Coefficient of Variation 24.6 |
| Cohort 2 | Pharmacokinetics of N6022 Over 7 Days | 367 h*ng/mL | Geometric Coefficient of Variation 14.2 |
| Cohort 3 | Pharmacokinetics of N6022 Over 7 Days | 811 h*ng/mL | Geometric Coefficient of Variation 11.3 |
| Placebo | Pharmacokinetics of N6022 Over 7 Days | 0 h*ng/mL | Geometric Coefficient of Variation 0 |