Safety, Tolerability and Pharmacokinetics of NN1731 in Healthy Volunteers

A Single-centre, Randomised, Placebo-controlled, Double-blind, Single-dose, Dose-escalation Trial to Assess the Safety, Tolerability and Pharmacokinetics of Ascending Intravenous Doses of an Activated Recombinant FVII Analogue (NN1731) in Healthy Japanese Male Subjects

This trial is conducted in Japan. The aim of this trial is to assess the safety and tolerability of activated recombinant human coagulation factor VII analogue (NN1731, vatreptacog alfa (activated)) in healthy Japanese male subjects. In addition, the pharmacokinetics of NN1731 will be examined

Study Overview

• Status: Completed
• Conditions: Healthy; Congenital Bleeding Disorder
• Intervention / Treatment: Drug: vatreptacog alfa (activated); Drug: vatreptacog alfa (activated); Drug: vatreptacog alfa (activated); Drug: vatreptacog alfa (activated); Drug: placebo; Drug: placebo; Drug: placebo; Drug: placebo

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 1

Contacts and Locations

Study Locations

• Japan
  • Tokyo, Japan, 130-0004

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 45 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Japanese male subjects, who are considered to be generally healthy based on assessment of medical history, physical examination and clinical laboratory data at screening, as judged by the Investigator or Sub-investigator
• Body Mass Index (BMI) between 18.0 and 27.0 kg/m^2 (inclusive)

Exclusion Criteria:

• Any clinical laboratory values deviated from the reference range at the laboratory (except for cases within physiological change) or any abnormal electrocardiogram (ECG) findings at the screening, as judged by the Investigator or Sub-investigator
• Presence or history of cancer or any clinically significant cardiac, respiratory, metabolic, renal, hepatic, gastrointestinal, endocrinological, dermatological, venereal, haematological, neurological, or psychiatric diseases or disorders
• Evidence of clinically relevant pathology or a potential thromboembolic risk as judged by the Investigator or Sub-investigator
• Presence or history of atherosclerosis, arteriosclerosis or thromboembolic events
• Any past history of migraine
• Overt bleeding, including from the gastrointestinal tract

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: vatreptacog alfa, 5 mcg/kg	Drug: vatreptacog alfa (activated); One single dose is injected i.v. over 2 minutes to 6 subjects, 5 mcg/kg; Drug: vatreptacog alfa (activated); One single dose is injected i.v. over 2 minutes to 6 subjects, 10 mcg/kg; Drug: vatreptacog alfa (activated); One single dose is injected i.v. over 2 minutes to 6 subjects, 20 mcg/kg; Drug: vatreptacog alfa (activated); One single dose is injected i.v. over 2 minutes to 6 subjects, 30 mcg/kg; Drug: placebo; Single dose is injected i.v. over 2 minutes to 2 subjects per dose level: 5 mcg/kg; Drug: placebo; Single dose is injected i.v. over 2 minutes to 2 subjects per dose level: 10 mcg/kg; Drug: placebo; Single dose is injected i.v. over 2 minutes to 2 subjects per dose level: 20 mcg/kg; Drug: placebo; Single dose is injected i.v. over 2 minutes to 2 subjects per dose level: 30 mcg/kg
Experimental: vatreptacog alfa, 10 mcg/kg	Drug: vatreptacog alfa (activated); One single dose is injected i.v. over 2 minutes to 6 subjects, 5 mcg/kg; Drug: vatreptacog alfa (activated); One single dose is injected i.v. over 2 minutes to 6 subjects, 10 mcg/kg; Drug: vatreptacog alfa (activated); One single dose is injected i.v. over 2 minutes to 6 subjects, 20 mcg/kg; Drug: vatreptacog alfa (activated); One single dose is injected i.v. over 2 minutes to 6 subjects, 30 mcg/kg; Drug: placebo; Single dose is injected i.v. over 2 minutes to 2 subjects per dose level: 5 mcg/kg; Drug: placebo; Single dose is injected i.v. over 2 minutes to 2 subjects per dose level: 10 mcg/kg; Drug: placebo; Single dose is injected i.v. over 2 minutes to 2 subjects per dose level: 20 mcg/kg; Drug: placebo; Single dose is injected i.v. over 2 minutes to 2 subjects per dose level: 30 mcg/kg
Experimental: vatreptacog alfa, 20 mcg/kg	Drug: vatreptacog alfa (activated); One single dose is injected i.v. over 2 minutes to 6 subjects, 5 mcg/kg; Drug: vatreptacog alfa (activated); One single dose is injected i.v. over 2 minutes to 6 subjects, 10 mcg/kg; Drug: vatreptacog alfa (activated); One single dose is injected i.v. over 2 minutes to 6 subjects, 20 mcg/kg; Drug: vatreptacog alfa (activated); One single dose is injected i.v. over 2 minutes to 6 subjects, 30 mcg/kg; Drug: placebo; Single dose is injected i.v. over 2 minutes to 2 subjects per dose level: 5 mcg/kg; Drug: placebo; Single dose is injected i.v. over 2 minutes to 2 subjects per dose level: 10 mcg/kg; Drug: placebo; Single dose is injected i.v. over 2 minutes to 2 subjects per dose level: 20 mcg/kg; Drug: placebo; Single dose is injected i.v. over 2 minutes to 2 subjects per dose level: 30 mcg/kg
Experimental: vatreptacog alfa, 30 mcg/kg	Drug: vatreptacog alfa (activated); One single dose is injected i.v. over 2 minutes to 6 subjects, 5 mcg/kg; Drug: vatreptacog alfa (activated); One single dose is injected i.v. over 2 minutes to 6 subjects, 10 mcg/kg; Drug: vatreptacog alfa (activated); One single dose is injected i.v. over 2 minutes to 6 subjects, 20 mcg/kg; Drug: vatreptacog alfa (activated); One single dose is injected i.v. over 2 minutes to 6 subjects, 30 mcg/kg; Drug: placebo; Single dose is injected i.v. over 2 minutes to 2 subjects per dose level: 5 mcg/kg; Drug: placebo; Single dose is injected i.v. over 2 minutes to 2 subjects per dose level: 10 mcg/kg; Drug: placebo; Single dose is injected i.v. over 2 minutes to 2 subjects per dose level: 20 mcg/kg; Drug: placebo; Single dose is injected i.v. over 2 minutes to 2 subjects per dose level: 30 mcg/kg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety (Physical Examination, Vital Signs, ECG, Haematology, Biochemistry, Urinalysis, Coagulation Factors, Coagulation-related Parameters, Injection Site Tolerability and Adverse Events (AE))	Any safety issue was reported as AE	between dosing and 2-3 weeks after dosing
Subjects With Anti-Vatreptacog Alfa Antibody	Post-dosing samples from subjects were evaluated for the presence of Anti-Vatreptacog alfa antibody	between dosing, 2-3 weeks after dosing, and 11-13 weeks after dosing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Vatreptacog Alfa Clot Activity: Area Under the FVIIa Activity-time Curve From Time 0 and up Until the Last Quantifiable Activity (AUC0-t)	AUC0-t was computed using the linear trapezoid rule. Plasma FVIIa clot activity at time 0 was calculated by log linear interpolation.	during 1-2 days after drug administration
Vatreptacog Alfa Clot Activity: Area Under the FVIIa Activity-time Curve From Time 0 to 24 h (AUC0-24)	Blood samples were collected at following time points: -30 min, -20 min, -10 min, 5 min, 10 min, 20 min, 30 min, 1 h, 2h, 3h, 4h, 5h, 8h, 12h and 24h to calculate area under the curve.	during 1-2 days after drug administration
Vatreptacog Alfa Clot Activity: Area Under the FVIIa Activity-time Curve From Time 0 h to Infinity (AUC 0-inf)	AUC0-inf = AUC0-t + (Ct / λz), Where Ct is the last quantifiable activity and t the time of Ct.	during 1-2 days after drug administration
Vatreptacog Alfa Clot Activity: Maximum FVIIa Activity (Cmax)		during 1-2 days after drug administration
Vatreptacog Alfa Clot Activity: FVIIa Activity Measured 5 Min After Administration of NN1731 (C5min)		during 1-2 days after drug administration
Vatreptacog Alfa Clot Activity: Back Extrapolated Estimate of the Initial FVIIa Activity (C0)		during 1-2 days after drug administration
Vatreptacog Alfa Clot Activity- Terminal Slope (λz)		during 1-2 days after drug administration
Vatreptacog Alfa Clot Activity: Terminal Half-life (t1/2)		during 1-2 days after drug administration
Vatreptacog Alfa Clot Activity- Total Clearance (CL)		during 1-2 days after drug administration
Vatreptacog Alfa Clot Activity- Apparent Volume of Distribution at Steady State (Vss)		during 1-2 days after drug administration
Vatreptacog Alfa Clot Activity- Initial Volume of Distribution (VD)		during 1-2 days after drug administration
Vatreptacog Alfa Clot Activity- Mean Residence Time (MRT)	Mean residence time of the unchanged drug in the systemic circulation	during 1-2 days after drug administration

Collaborators and Investigators

• Sponsor: Novo Nordisk A/S

Publications and helpful links

Helpful Links

• Clinical Trials at Novo Nordisk

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): July 1, 2009
• Study Completion (Actual): July 1, 2009

Study Registration Dates

• First Submitted: January 13, 2009
• First Submitted That Met QC Criteria: January 13, 2009
• First Posted (Estimate): January 14, 2009

Study Record Updates

• Last Update Posted (Estimate): January 5, 2015
• Last Update Submitted That Met QC Criteria: December 12, 2014
• Last Verified: December 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Blood Coagulation Disorders
• Other Study ID Numbers: NN1731-3604; JapicCTI-090681 (Registry Identifier: JAPIC)