Safety, Tolerability and Pharmacokinetics of NN1731 in Healthy Volunteers

Study Overview
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Brief Summary
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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

Official Title
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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

Conditions
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Healthy, Congenital Bleeding Disorder

Intervention / Treatment
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* Drug: vatreptacog alfa (activated)
* Drug: vatreptacog alfa (activated)
* Drug: vatreptacog alfa (activated)
* Drug: vatreptacog alfa (activated)
* Drug: placebo
* Drug: placebo
* Drug: placebo
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

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

What is the study measuring?
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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 |