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

• Sponsor: Nivalis Therapeutics, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01339897
• Collaborator: (none)
• Enrollment: 25
• Location: 1
• Arms: 4
• Duration (Months): 4
• Patients Per Site Per Month: 6.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: 5 mg/N6022; Drug: Placebo; Drug: 10mg/N6022; Drug: 20mg/N6022	Phase 1

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 Design

• Study Type: Interventional
• Actual Enrollment: 25 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Apr 1, 2011
• Actual Primary Completion Date: Aug 1, 2011
• Actual Study Completion Date: Aug 1, 2011

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Pharmacokinetics of N6022 [Day 1, 24 hours]

   N6022 AUC0-tau measurements from Day 1

2. Pharmacokinetics of N6022 Over 7 Days [Day 7, 24 hours]

   Analysis of N6022 AUC0-tau values from Study Day 7

3. Pharmacokinetics of N6022 on Study Day 1 [Day 1, 24 hours]

   Analysis of N6022 Cmax values on Study Day 1

4. Pharmacokinetics of N6022 Cmax Values on Study Day 7 [Day 7, 24 hours]

   Pharmacokinetic Analysis of N6022 Cmax values on Study Day 7

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts 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.).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Parexel International	Baltimore	Maryland	United States	21225

Sponsors and Collaborators

• Nivalis Therapeutics, Inc.

Investigators

• Principal Investigator: Ronald Goldwater, MDCM, MSc(A), Parexel

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Nivalis Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT01339897
• Other Study ID Numbers: N6022-1H1-03
• First Posted: Apr 21, 2011
• Last Update Posted: Jan 19, 2015
• Last Verified: Jan 1, 2015

• Keywords provided by Nivalis Therapeutics, Inc.: N6022, GSNORi

Study Results

Participant Flow

Recruitment Details	Recruitment occurred between 06April2011 and 09August2011. This study was done at a single Phase 1 site.

Arm/Group Title	5 mg/N6022	Placebo	10 mg/N6022	20 mg/N6022
Arm/Group Description	Active Group- 5 mg by IV administration (5 mg/minute)	Non-Active	Active Group- 10 mg by IV administration (5 mg/minute)	Active Group- 20 mg by IV administration (5 mg/minute)
Period Title: Overall Study
STARTED	7	6	6	6
COMPLETED	6	6	6	5
NOT COMPLETED	1	0	0	1

Baseline Characteristics

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Placebo	Total
Arm/Group Description	N6022 - Active 5 mg	N6022 - Active 10 mg	N6022 - Active 20 mg	Non-Active	Total of all reporting groups
Overall Participants	7	6	6	6	25
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	7 100%	6 100%	6 100%	6 100%	25 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	32	31	35	35	33
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%	0 0%	0 0%
Male	7 100%	6 100%	6 100%	6 100%	25 100%
Region of Enrollment (participants) [Number]
United States	7 100%	6 100%	6 100%	6 100%	25 100%

Outcome Measures

1. Primary Outcome

Title	Safety of Escalating Multiple Doses of N6022 in Healthy Subjects
Description	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

Outcome Measure Data

Analysis Population Description

Any subject that received any dose of N6022 or placebo.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Placebo
Arm/Group Description	N6022 - Active 5 mg	N6022 Active - 10 mg	N6022 - Active 20 mg	Non-Active
Measure Participants	7	6	6	6
Number of subjects on study	7 100%	6 100%	6 100%	6 100%
Early Termination	1 14.3%	0 0%	1 16.7%	0 0%
Treatment related AE	0 0%	0 0%	1 16.7%	0 0%

2. Secondary Outcome

Title	Pharmacokinetics of N6022
Description	N6022 AUC0-tau measurements from Day 1
Time Frame	Day 1, 24 hours

Outcome Measure Data

Analysis Population Description

Any subject that completed N6022 or placebo PK sampling

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Placebo
Arm/Group Description	N6022 Active - 5 mg	N6022 Active - 10 mg	N6022 Active - 20 mg	Non-Active
Measure Participants	7	6	6	6
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	138 (13.0)	334 (21.1)	669 (16.9)	0 (0)

3. Secondary Outcome

Title	Pharmacokinetics of N6022 Over 7 Days
Description	Analysis of N6022 AUC0-tau values from Study Day 7
Time Frame	Day 7, 24 hours

Outcome Measure Data

Analysis Population Description

N6022 AUC0-tau values from Study Day 7

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Placebo
Arm/Group Description	N6022 Active - 5 mg	N6022 Active - 10 mg	N6022 Active - 20 mg	Non-Active
Measure Participants	6	6	5	6
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	149 (24.6)	367 (14.2)	811 (11.3)	0 (0)

4. Secondary Outcome

Title	Pharmacokinetics of N6022 on Study Day 1
Description	Analysis of N6022 Cmax values on Study Day 1
Time Frame	Day 1, 24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Placebo
Arm/Group Description	N6022 Active - 5 mg	N6022 Active - 10 mg	N6022 Active - 20 mg	Non-Active
Measure Participants	7	6	6	6
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	465 (69.8)	1270 (95.6)	1400 (86.2)	0 (0)

5. Secondary Outcome

Title	Pharmacokinetics of N6022 Cmax Values on Study Day 7
Description	Pharmacokinetic Analysis of N6022 Cmax values on Study Day 7
Time Frame	Day 7, 24 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Placebo
Arm/Group Description	N6022 Active - 5 mg	N6022 Active - 10 mg	N6022 Active - 20 mg	Non-Active
Measure Participants	6	6	5	6
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	287 (89.8)	1110 (34.1)	2320 (13.5)	0 (0)

Adverse Events

Time Frame	7 Days
Arm/Group Title	Cohort 1		Cohort 2		Cohort 3		Placebo
Arm/Group Description	N6022 - Active 5 mg		N6022 Active - 10 mg		N6022 - Active 20 mg		Non-Active
All Cause Mortality
	Cohort 1		Cohort 2		Cohort 3		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Cohort 1		Cohort 2		Cohort 3		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/7 (0%)		0/6 (0%)		0/6 (0%)		0/6 (0%)
Other (Not Including Serious) Adverse Events
	Cohort 1		Cohort 2		Cohort 3		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/7 (100%)		2/6 (33.3%)		4/6 (66.7%)		5/6 (83.3%)
Cardiac disorders
Ventricular Arrythmia	1/7 (14.3%)	1	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Ear and labyrinth disorders
Vertigo Positional	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Gastrointestinal disorders
Abdominal Pain	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0
Abdominal Discomfort	0/7 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Diarrhea	0/7 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Nausea	0/7 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Aphthous Stomatitis	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
General disorders
Fatigue	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0
Injection Site Extravasation	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0
Pain	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0
Vessel Puncture Site Hematoma	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0
Injection Site Induration	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Injection Site Pain	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Infections and infestations
Otitis Externa	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0
Upper Respiratory tract Infection	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0
Injury, poisoning and procedural complications
Traumatic Hematoma	0/7 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0	0/6 (0%)	0
Investigations
Blood Magnesium Abnormal	0/7 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Musculoskeletal and connective tissue disorders
Musculosketetal Pain	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0
Pain in Extremity	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Nervous system disorders
Dizziness	1/7 (14.3%)	1	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Pre-syncope	0/7 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Headache	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1
Respiratory, thoracic and mediastinal disorders
Nasal Congestion	0/7 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1	0/6 (0%)	0
Skin and subcutaneous tissue disorders
Dermatitis	1/7 (14.3%)	1	0/6 (0%)	0	0/6 (0%)	0	0/6 (0%)	0
Contact Dermatitis	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	2/6 (33.3%)	2
Vascular disorders
Phlebitis Superficial	0/7 (0%)	0	0/6 (0%)	0	0/6 (0%)	0	1/6 (16.7%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The investigator agrees with the use of results of the clinical study for the purposes of national and international registration, publication, and information for medical and pharmaceutical professionals. If necessary, the competent authorities will be notified of the investigator's name, address, qualifications, and extent of involvement. An investigator shall not publish any data (poster, abstract, paper, etc.) without having consulted with the Sponsor in advance.