Safety and Efficacy of NNC-0156-0000-0009 After Long-Term Exposure in Patients With Haemophilia B: An Extension to Trials NN7999-3747 and NN7999-3773

Study Overview
=================
Brief Summary
-----------------
This trial is conducted in Asia, Europe, Japan, North America and South Africa. The aim is to evaluate the safety and efficacy of nonacog beta pegol (NNC-0156-0000-0009) after long-term exposure in patients with haemophilia B. This trial is an extension to trials NN7999-3747 (NCT01333111/paradigm™ 2) and NN7999-3773 (NCT01386528/paradigm™ 3).

Official Title
-----------------
Safety and Efficacy of NNC-0156-0000-0009 After Long-Term Exposure in Patients With Haemophilia B

Conditions
-----------------
Congenital Bleeding Disorder, Haemophilia B

Intervention / Treatment
-----------------
* Drug: nonacog beta pegol
* Drug: nonacog beta pegol
* Drug: nonacog beta pegol


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Previous participation in NN7999-3747 (NCT01333111) and/or NN7999-3773 Exclusion Criteria: Known history of FIX inhibitors based on existing medical records, laboratory report reviews and patient and LAR (legal acceptable representative) interviews Current FIX inhibitors above or equal to 0.6 BU (Bethesda Units) Congenital or acquired coagulation disorders other than haemophilia B Previous arterial thrombotic events (e.g. myocardial infarction and intracranial thrombosis) or previous deep venous thrombosis or pulmonary embolism (as defined by available medical records) Any disease (liver, kidney, inflammatory and mental disorders included) or condition which, according to the Investigator's (trial physician) judgement, could imply a potential hazard to the patient, interfere with trial participation, or interfere with trial outcome

Ages Eligible for Study
-----------------
Minimum Age: 13 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prophylaxis, high dose (once weekly)<br> | Drug: nonacog beta pegol<br>* One single dose administered intravenously (into the vein) once weekly. Patients will receive instruction on how to treat any bleeding episode they may experience.<br>* Other names: NNC-0156-0000-0009;|
| Experimental: Prophylaxis, low dose (once weekly)<br> | Drug: nonacog beta pegol<br>* One single dose administered intravenously (into the vein) once weekly. Patients will receive instruction on how to treat any bleeding episode they may experience.<br>* Other names: NNC-0156-0000-0009;|
| Experimental: On-demand<br> | Drug: nonacog beta pegol<br>* One single dose administered intravenously (into the vein). Patients will treat themselves with either a low or a high dose dependent on the severity of the bleeding episode.<br>* Other names: NNC-0156-0000-0009;|
| Experimental: Prophylaxis, high dose (every second week)<br> | Drug: nonacog beta pegol<br>* One single dose administered intravenously (into the vein) every second week. Patients will receive instruction on how to treat any bleeding episode they may experience.<br>* Other names: NNC-0156-0000-0009;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Inhibitory Antibodies Against FIX Defined as Titre Above or Equal to 0.6 BU (Bethesda Units) | The primary endpoint was incidence of inhibitors against coagulation factor nine (FIX) defined as titre ≥0.6 Bethesda unit (BU). Number of subjects who developed inhibitors against FIX are reported. | From Day 1 up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| FIX Trough Levels | During the trial, the pre-dose FIX levels was measured with the one-stage clotting assay. Measurements taken at least 5 days and no more than 10 days after last dose as well as at least 14 days after last bleeding episode were included in this analysis. The mean FIX trough levels were estimated based on the mixed effects model on the log-transformed plasma concentration with subject as a random effect. The mean FIX trough level was presented back-transformed to the natural scale. | From Day 1 up to 2 years | 
| Incidence of Adverse Events (AEs) | AEs were summarized by frequency of events and frequency of patients with any event. Incidence of AEs was expressed as number of AEs per subject years of exposure (total number of events /total time in trial). | From Day 1 up to 2 years | 
| Incidence of Serious Adverse Events (SAEs) | AEs were summarized by frequency of events and frequency of patients with any event. Incidence of serious AEs was expressed as number of serious AEs per subject years of exposure (total number of events /total time in trial). | From Day 1 up to 2 years | 
| Haemostatic Effect of Nonacog Beta Pegol When Used for Treatment of Bleeding Episodes, Assessed as Success/Failure Based on a Four-point Scale for Haemostatic Response (Excellent, Good, Moderate, Poor) | The haemostatic effect was evaluated by a four-point scale where an excellent or good outcome translated into a successful treatment, and a moderate or poor outcome was considered a treatment failure. The values mentioned below do not include bleeds with missing response. | From Day 1 up to 2 years | 
| Number of Bleeding Episodes During Routine Prophylaxis | Annualized bleeding rate is the total number of bleeding episodes/total exposure time. It is analysed by a Poisson regression model with dose as a factor allowing for over-dispersion and using treatment duration as an offset. Median annualized bleeding rate is the median of individual annualized bleeding rates. Numbers are based on the treatment arm at the time of each bleed. | From Day 1 up to 2 years |