A Safety Study Evaluating N6022 in Multiple-Ascending Doses in Healthy Subjects

A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Multiple-Ascending Dose Study Evaluating the Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Effects of N6022 in Healthy Subjects

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: 5 mg/N6022; Drug: Placebo; Drug: 10mg/N6022; Drug: 20mg/N6022

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.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21225
      • PAREXEL International

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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.).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 5 mg/N6022; Injectable formulation, given at doses per cohort of 5 mg given QD each day over 7 days.	Drug: 5 mg/N6022; Intravenous formulation, given at doses of 5 mg once each day over 7 days.; Other Names: N6022; GSNOR Inhibitor
Placebo Comparator: Placebo; Injectable formulation normal saline	Drug: Placebo; Same administration procedures as active; Other Names: Normal Saline
Active Comparator: 10mg/N6022; Injectable formulation, given at doses of 10 mg given QD each day over 7 days.	Drug: 10mg/N6022; Intravenous formulation given at doses of 10 mg once each day over 7 days.; Other Names: N6022; GSNOR Inhibitor
Active Comparator: 20mg/N6022; Injectable formulation, given at doses per cohort of 20 mg given QD each day over 7 days.	Drug: 20mg/N6022; Intravenous formulation given at doses of 20 mg once each day over 7 days.; Other Names: N6022; GSNOR Inhibitor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	Over 7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics of N6022	N6022 AUC0-tau measurements from Day 1	Day 1, 24 hours
Pharmacokinetics of N6022 Over 7 Days	Analysis of N6022 AUC0-tau values from Study Day 7	Day 7, 24 hours
Pharmacokinetics of N6022 on Study Day 1	Analysis of N6022 Cmax values on Study Day 1	Day 1, 24 hours
Pharmacokinetics of N6022 Cmax Values on Study Day 7	Pharmacokinetic Analysis of N6022 Cmax values on Study Day 7	Day 7, 24 hours

Collaborators and Investigators

• Sponsor: Nivalis Therapeutics, Inc.
• Investigators: Principal Investigator: Ronald Goldwater, MDCM, MSc(A), Parexel

Study record dates

Study Major Dates

• Study Start: April 1, 2011
• Primary Completion (Actual): August 1, 2011
• Study Completion (Actual): August 1, 2011

Study Registration Dates

• First Submitted: April 19, 2011
• First Submitted That Met QC Criteria: April 20, 2011
• First Posted (Estimate): April 21, 2011

Study Record Updates

• Last Update Posted (Estimate): January 19, 2015
• Last Update Submitted That Met QC Criteria: January 15, 2015
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: N6022, GSNORi
• Other Study ID Numbers: N6022-1H1-03