paradigm™ 4: 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

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01395810
• Collaborator: (none)
• Enrollment: 71
• Locations: 49
• Arms: 4
• Actual Duration (Months): 23.5
• Patients Per Site: 1.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Congenital Bleeding Disorder; Haemophilia B	Drug: nonacog beta pegol; Drug: nonacog beta pegol; Drug: nonacog beta pegol	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 71 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Safety and Efficacy of NNC-0156-0000-0009 After Long-Term Exposure in Patients With Haemophilia B
• Actual Study Start Date: Apr 15, 2012
• Actual Primary Completion Date: Mar 30, 2014
• Actual Study Completion Date: Mar 30, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Prophylaxis, high dose (once weekly)	Drug: nonacog beta pegol; One single dose administered intravenously (into the vein) once weekly. Patients will receive instruction on how to treat any bleeding episode they may experience.; Other Names: NNC-0156-0000-0009
Experimental: Prophylaxis, low dose (once weekly)	Drug: nonacog beta pegol; One single dose administered intravenously (into the vein) once weekly. Patients will receive instruction on how to treat any bleeding episode they may experience.; Other Names: NNC-0156-0000-0009
Experimental: On-demand	Drug: nonacog beta pegol; 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.; Other Names: NNC-0156-0000-0009
Experimental: Prophylaxis, high dose (every second week)	Drug: nonacog beta pegol; 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.; Other Names: NNC-0156-0000-0009

Outcome Measures

Primary Outcome Measures

1. Incidence of Inhibitory Antibodies Against FIX Defined as Titre Above or Equal to 0.6 BU (Bethesda Units) [From Day 1 up to 2 years]

   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.

Secondary Outcome Measures

1. 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) [From Day 1 up to 2 years]

   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.

2. Number of Bleeding Episodes During Routine Prophylaxis [From Day 1 up to 2 years]

   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.

3. FIX Trough Levels [From Day 1 up to 2 years]

   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.

4. Incidence of Adverse Events (AEs) [From Day 1 up to 2 years]

   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).

5. Incidence of Serious Adverse Events (SAEs) [From Day 1 up to 2 years]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 13 Years to 70 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Los Angeles	California	United States	90027-6016
2	Novo Nordisk Investigational Site	San Francisco	California	United States	94143
3	Novo Nordisk Investigational Site	Washington	District of Columbia	United States	20007
4	Novo Nordisk Investigational Site	Jacksonville	Florida	United States	32207
5	Novo Nordisk Investigational Site	Augusta	Georgia	United States	30912
6	Novo Nordisk Investigational Site	Iowa City	Iowa	United States	52242
7	Novo Nordisk Investigational Site	Baltimore	Maryland	United States	21287
8	Novo Nordisk Investigational Site	Minneapolis	Minnesota	United States	55404
9	Novo Nordisk Investigational Site	Omaha	Nebraska	United States	68198-5456
10	Novo Nordisk Investigational Site	Newark	New Jersey	United States	07102
11	Novo Nordisk Investigational Site	New York	New York	United States	10029
12	Novo Nordisk Investigational Site	Syracuse	New York	United States	13210
13	Novo Nordisk Investigational Site	Houston	Texas	United States	77030
14	Novo Nordisk Investigational Site	Wien		Austria	1090
15	Novo Nordisk Investigational Site	Bron Cedex		France	69677
16	Novo Nordisk Investigational Site	Kremlin-Bicêtre		France	94270
17	Novo Nordisk Investigational Site	Bonn		Germany	53127
18	Novo Nordisk Investigational Site	Duisburg		Germany	47051
19	Novo Nordisk Investigational Site	Giessen		Germany	35392
20	Novo Nordisk Investigational Site	Hannover		Germany	30625
21	Novo Nordisk Investigational Site	Athens		Greece	GR-11527
22	Novo Nordisk Investigational Site	Firenze		Italy	50134
23	Novo Nordisk Investigational Site	Milano		Italy	20124
24	Novo Nordisk Investigational Site	Kashihara-shi, Nara		Japan	634 8522
25	Novo Nordisk Investigational Site	Kawasaki-shi, Kanagawa		Japan	216-8511
26	Novo Nordisk Investigational Site	Nagoya-shi, Aichi		Japan	466 8560
27	Novo Nordisk Investigational Site	Nishinomiya-shi		Japan	663 8051
28	Novo Nordisk Investigational Site	Shinjuku-ku, Tokyo		Japan	160 0023
29	Novo Nordisk Investigational Site	Suginami-ku, Tokyo		Japan	167 0035
30	Novo Nordisk Investigational Site	Skopje		Macedonia, The Former Yugoslav Republic of	1000
31	Novo Nordisk Investigational Site	Kuala Lumpur		Malaysia	50400
32	Novo Nordisk Investigational Site	Utrecht		Netherlands	3584 CX
33	Novo Nordisk Investigational Site	Timisoara	Timis	Romania	300011
34	Novo Nordisk Investigational Site	Moscow		Russian Federation	105077
35	Novo Nordisk Investigational Site	Saint-Petersburg		Russian Federation	191119
36	Novo Nordisk Investigational Site	Parktown Johannesburg	Gauteng	South Africa	2193
37	Novo Nordisk Investigational Site	Madrid		Spain	28046
38	Novo Nordisk Investigational Site	Valencia		Spain	46026
39	Novo Nordisk Investigational Site	Taipei		Taiwan	100
40	Novo Nordisk Investigational Site	Bangkok		Thailand	10400
41	Novo Nordisk Investigational Site	Ankara		Turkey	06500
42	Novo Nordisk Investigational Site	Kayseri		Turkey	38010
43	Novo Nordisk Investigational Site	Konya		Turkey	42090
44	Novo Nordisk Investigational Site	Basingstoke		United Kingdom	RG24 9NA
45	Novo Nordisk Investigational Site	Cardiff		United Kingdom	CF14 4XW
46	Novo Nordisk Investigational Site	London		United Kingdom	NW3 2QG
47	Novo Nordisk Investigational Site	London		United Kingdom	SE1 7EH
48	Novo Nordisk Investigational Site	Manchester		United Kingdom	M13 9WL
49	Novo Nordisk Investigational Site	Oxford		United Kingdom	OX3 7LJ

Sponsors and Collaborators

• Novo Nordisk A/S

Investigators

• Study Director: Global Clinical Registry (GCR, 1452), Novo Nordisk A/S

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Clinical Trials at Novo Nordisk

Publications

• Young G, Collins P, Tehranchi R, Chuansumrit A, Hanabusa H, Lentz SR, Mahlangu J, Mauser-Bunschoten E, Negrier C, Oldenburg J, Patiroglu T, Santagostino E, Zak M, Abdul Karim F. Safety and efficacy of nonacog beta pegol (N9-GP) for prophylaxis and treatment of bleeding episodes in previously-treated patients with hemophilia B: results from an extension trial. American Society of Hematology - 56th Annual Meeting (ASH) in San Francisco, CA, US

• Responsible Party: Novo Nordisk A/S
• ClinicalTrials.gov Identifier: NCT01395810
• Other Study ID Numbers: NN7999-3775; 2010-023072-17; U1111-1121-5408; JapicCTI-121812
• First Posted: Jul 18, 2011
• Last Update Posted: May 9, 2018
• Last Verified: Apr 1, 2018

• Additional relevant MeSH terms: Hemostatic Disorders; Hemophilia A; Hemophilia B; Blood Coagulation Disorders

Study Results

Participant Flow

Recruitment Details	The trial was conducted at 41 sites in 15 countries as follows: France: 1 site; Germany: 3 sites; Italy: 2 sites; Japan: 4 sites; Macedonia: 2 sites; Malaysia: 1 site; Netherlands: 1 site; Romania: 1 site, Russia: 1 site; South Africa: 1 site; Taiwan: 1 site, Thailand: 2 sites; Turkey: 3 sites; United Kingdom: 5 sites; United States: 13 sites
Pre-assignment Detail	A total of 71 unique subjects were dosed during this trial. During the trial, subjects were free to switch between treatment arms if agreed between the investigator and the subject. Subjects who switched arms were represented in multiple arms.

Arm/Group Title	Prophylaxis 10 IU/kg	Prophylaxis 40 IU/kg	Prophylaxis 80 IU/kg	On-demand
Arm/Group Description	Subjects were given 10 IU/kg weekly nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an intravenous (i.v.) bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	Subjects were given 40 IU/kg weekly nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	Subjects were dosed with 80 IU/kg every second week. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	Subjects in the on-demand group were administered with the single dose of 40 IU/kg of nonacog beta pegol. The recommended dose for treatment of a mild or moderate bleeding episode, for example a joint bleed, was a single dose of 40 IU/kg nonacog beta pegol. If there was no observed effect of 40 IU/kg, the investigator was to be contacted prior to administration of the second dose of 40 IU/kg. The recommended dose for severe bleeds was 80 IU/kg nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject.
Period Title: Overall Study
STARTED	18	48	0	5
After Switching the Arms	21	52	2	5
COMPLETED	16	44	0	5
NOT COMPLETED	2	4	0	0

Baseline Characteristics

Arm/Group Title	Prophylaxis 10 IU/kg	Prophylaxis 40 IU/kg	Prophylaxis 80 IU/kg	On-demand	Total
Arm/Group Description	Subjects were given 10 IU/kg weekly nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	Subjects were given 40 IU/kg weekly nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	Subjects were dosed with 80 IU/kg every second week. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	Subjects in the on-demand group were administered with the single dose of 40 IU/kg of nonacog beta pegol. The recommended dose for treatment of a mild or moderate bleeding episode, for example a joint bleed, was a single dose of 40 IU/kg nonacog beta pegol. If there was no observed effect of 40 IU/kg, the investigator was to be contacted prior to administration of the second dose of 40 IU/kg. The recommended dose for severe bleeds was 80 IU/kg nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject.	Total of all reporting groups
Overall Participants	18	48	0	5	71
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	32.2 (13.6)	31.4 (14.4)	37.6 (15.4)	32.0 (14.2)
Age, Customized (Number) [Number]
13 - 17 years	3 16.7%	12 25%	0 NaN	15 300%
18 - 70 years	15 83.3%	36 75%	5 Infinity	56 1120%
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 NaN	0 0%	0 0%
Male	18 100%	48 100%	0 NaN	5 100%	71 100%

Outcome Measures

1. Primary Outcome

Title	Incidence of Inhibitory Antibodies Against FIX Defined as Titre Above or Equal to 0.6 BU (Bethesda Units)
Description	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.
Time Frame	From Day 1 up to 2 years

Outcome Measure Data

Analysis Population Description

Safety Analysis Set consisted of all subjects exposed to nonacog beta pegol. Subjects who switched arms were represented in multiple columns.

Arm/Group Title	Prophylaxis 10 IU/kg	Prophylaxis 40 IU/kg	Prophylaxis 80 IU/kg	On-demand
Arm/Group Description	Subjects were given 10 IU/kg weekly nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	Subjects were given 40 IU/kg weekly nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	Subjects were dosed with 80 IU/kg every second week. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	Subjects in the on-demand group were administered with the single dose of 40 IU/kg of nonacog beta pegol. The recommended dose for treatment of a mild or moderate bleeding episode, for example a joint bleed, was a single dose of 40 IU/kg nonacog beta pegol. If there was no observed effect of 40 IU/kg, the investigator was to be contacted prior to administration of the second dose of 40 IU/kg. The recommended dose for severe bleeds was 80 IU/kg nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject.
Measure Participants	21	52	2	5
Number [Patients with inhibitory antibodies]	0	0	0	0

2. Secondary Outcome

Title	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)
Description	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.
Time Frame	From Day 1 up to 2 years

Outcome Measure Data

Analysis Population Description

Full analysis set consisted of all subjects exposed to nonacog beta pegol. Subjects who switched arms were represented in multiple columns.

Arm/Group Title	Prophylaxis 10 IU/kg	Prophylaxis 40 IU/kg	Prophylaxis 80 IU/kg	On-demand	Total
Arm/Group Description	Subjects were given 10 IU/kg weekly nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	Subjects were given 40 IU/kg weekly nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	Subjects were dosed with 80 IU/kg every second week. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	Subjects in the on-demand group were administered with the single dose of 40 IU/kg of nonacog beta pegol. The recommended dose for treatment of a mild or moderate bleeding episode, for example a joint bleed, was a single dose of 40 IU/kg nonacog beta pegol. If there was no observed effect of 40 IU/kg, the investigator was to be contacted prior to administration of the second dose of 40 IU/kg. The recommended dose for severe bleeds was 80 IU/kg nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject.	Subjects received nonacog beta pegol as prophylaxis treatment or on-demand treatment. Subjects in the prophylaxis treatment received either 10 IU/kg once weekly, 40 IU/kg once weekly or 80 IU/kg once every second week. Subjects in the on-demand group were administered with a single dose of 40 IU/kg of nonacog beta pegol. Subjects with on-demand treatment and prophylaxis treatments who experienced a bleeding episode were to be treated with single dose of 40 IU/kg unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects were free to switch between treatment arms if agreed between the investigator and the subject.
Measure Participants	21	52	2	5	71
Measure Bleeding episodes	35	98	1	73	207
Success	97.1	94.8	100	93.2	94.6
Failure	2.9	5.2	0	6.8	5.4

3. Secondary Outcome

Title	Number of Bleeding Episodes During Routine Prophylaxis
Description	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.
Time Frame	From Day 1 up to 2 years

Outcome Measure Data

Analysis Population Description

Full analysis set consisted of all subjects exposed to nonacog beta pegol. Subjects who switched arms were represented in multiple columns.

Arm/Group Title	Prophylaxis 10 IU/kg	Prophylaxis 40 IU/kg	Prophylaxis 80 IU/kg
Arm/Group Description	Subjects were given 10 IU/kg weekly nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	Subjects were given 40 IU/kg weekly nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	Subjects were dosed with 80 IU/kg every second week. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.
Measure Participants	21	52	2
Median (Inter-Quartile Range) [bleeds/patient/year]	1.36	1.00	0

4. Secondary Outcome

Title	FIX Trough Levels
Description	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.
Time Frame	From Day 1 up to 2 years

Outcome Measure Data

Analysis Population Description

Full analysis set consisted of all subjects exposed to nonacog beta pegol. This endpoint was analysed only for the prophylaxis arms (i.e.,10 IU/kg, 40 IU/kg). No pre-dose measurements were collected for patients on 80 IU/kg every second week prophylaxis.

Arm/Group Title	Prophylaxis 10 IU/kg	Prophylaxis 40 IU/kg
Arm/Group Description	Subjects were given 10 IU/kg weekly nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	Subjects were given 40 IU/kg weekly nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.
Measure Participants	21	52
Mean (95% Confidence Interval) [IU/mL]	0.098	0.213

5. Secondary Outcome

Title	Incidence of Adverse Events (AEs)
Description	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).
Time Frame	From Day 1 up to 2 years

Outcome Measure Data

Analysis Population Description

Safety Analysis Set consisted of all subjects who were exposed to nonacog beta pegol. Subjects who switched arms were represented in multiple columns.

Arm/Group Title	Prophylaxis 10 IU/kg	Prophylaxis 40 IU/kg	Prophylaxis 80 IU/kg	On-demand
Arm/Group Description	Subjects were given 10 IU/kg weekly nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	Subjects were given 40 IU/kg weekly nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	Subjects were dosed with 80 IU/kg every second week. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	Subjects in the on-demand group were administered with the single dose of 40 IU/kg of nonacog beta pegol. The recommended dose for treatment of a mild or moderate bleeding episode, for example a joint bleed, was a single dose of 40 IU/kg nonacog beta pegol. If there was no observed effect of 40 IU/kg, the investigator was to be contacted prior to administration of the second dose of 40 IU/kg. The recommended dose for severe bleeds was 80 IU/kg nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject.
Measure Participants	21	52	2	5
Number [Events per subject year of exposure]	2.4	1.9	0	3.2

6. Secondary Outcome

Title	Incidence of Serious Adverse Events (SAEs)
Description	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).
Time Frame	From Day 1 up to 2 years

Outcome Measure Data

Analysis Population Description

Safety Analysis set consisted of all subjects exposed to nonacog beta pegol. Subjects who switched arms were represented in multiple columns.

Arm/Group Title	Prophylaxis 10 IU/kg	Prophylaxis 40 IU/kg	Prophylaxis 80 IU/kg	On-demand
Arm/Group Description	Subjects were given 10 IU/kg weekly nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	Subjects were given 40 IU/kg weekly nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	Subjects were dosed with 80 IU/kg every second week. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.	Subjects in the on-demand group were administered with the single dose of 40 IU/kg of nonacog beta pegol. The recommended dose for treatment of a mild or moderate bleeding episode, for example a joint bleed, was a single dose of 40 IU/kg nonacog beta pegol. If there was no observed effect of 40 IU/kg, the investigator was to be contacted prior to administration of the second dose of 40 IU/kg. The recommended dose for severe bleeds was 80 IU/kg nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject.
Measure Participants	21	52	2	5
Number [Events per subject year of exposure]	0.1	0.1	0	0

Adverse Events

Time Frame	Adverse Events (AEs) from baseline visit (visit 1) and until one week after last treatment with nonacog beta pegol (±2 days) (up to 2 years)
Adverse Event Reporting Description	The safety analysis set consists of all patients exposed to nonacog beta pegol.
Arm/Group Title	Prophylaxis 10 U/kg		Prophylaxis 40 U/kg		Prophylaxis 80 U/kg		On-demand
Arm/Group Description	Subjects were given 10 IU/kg weekly nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an intravenous (i.v.) bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.		Subjects were given 40 IU/kg weekly nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.		Subjects were dosed with 80 IU/kg every second week. Subjects were free to switch between treatment arms if agreed between the investigator and the subject. Administration of the appropriate volume of nonacog beta pegol was given as an i.v. bolus injection. The maximum injection rate was 4 mL/min. Subjects on prophylaxis who experienced a bleeding episode were to treat the bleeding episode with a single dose of 40 IU/kg, unless the bleeding episode was severe in which case it was to be treated with 80 IU/kg.		Subjects in the on-demand group were administered with the single dose of 40 IU/kg of nonacog beta pegol. The recommended dose for treatment of a mild or moderate bleeding episode, for example a joint bleed, was a single dose of 40 IU/kg nonacog beta pegol. If there was no observed effect of 40 IU/kg, the investigator was to be contacted prior to administration of the second dose of 40 IU/kg. The recommended dose for severe bleeds was 80 IU/kg nonacog beta pegol. Subjects were free to switch between treatment arms if agreed between the investigator and the subject.
All Cause Mortality
	Prophylaxis 10 U/kg		Prophylaxis 40 U/kg		Prophylaxis 80 U/kg		On-demand
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Prophylaxis 10 U/kg		Prophylaxis 40 U/kg		Prophylaxis 80 U/kg		On-demand
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/21 (4.8%)		5/52 (9.6%)		0/2 (0%)		0/5 (0%)
Gastrointestinal disorders
Faecaloma	1/21 (4.8%)	1	0/52 (0%)	0	0/2 (0%)	0	0/5 (0%)	0
Infections and infestations
Gastroenteritis	0/21 (0%)	0	1/52 (1.9%)	1	0/2 (0%)	0	0/5 (0%)	0
Post procedural infection	0/21 (0%)	0	1/52 (1.9%)	1	0/2 (0%)	0	0/5 (0%)	0
Injury, poisoning and procedural complications
Femur fracture	0/21 (0%)	0	1/52 (1.9%)	1	0/2 (0%)	0	0/5 (0%)	0
Road traffic accident	0/21 (0%)	0	1/52 (1.9%)	1	0/2 (0%)	0	0/5 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatocellular carcinoma	0/21 (0%)	0	1/52 (1.9%)	1	0/2 (0%)	0	0/5 (0%)	0
Other (Not Including Serious) Adverse Events
	Prophylaxis 10 U/kg		Prophylaxis 40 U/kg		Prophylaxis 80 U/kg		On-demand
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/21 (38.1%)		8/52 (15.4%)		0/2 (0%)		5/5 (100%)
Eye disorders
Asthenopia	0/21 (0%)	0	0/52 (0%)	0	0/2 (0%)	0	1/5 (20%)	1
Gastrointestinal disorders
Dental caries	2/21 (9.5%)	2	0/52 (0%)	0	0/2 (0%)	0	0/5 (0%)	0
General disorders
Chest discomfort	0/21 (0%)	0	0/52 (0%)	0	0/2 (0%)	0	1/5 (20%)	1
Influenza like illness	1/21 (4.8%)	1	1/52 (1.9%)	1	0/2 (0%)	0	1/5 (20%)	1
Pain	0/21 (0%)	0	1/52 (1.9%)	1	0/2 (0%)	0	1/5 (20%)	3
Swelling	0/21 (0%)	0	0/52 (0%)	0	0/2 (0%)	0	1/5 (20%)	1
Infections and infestations
Bronchitis	0/21 (0%)	0	0/52 (0%)	0	0/2 (0%)	0	1/5 (20%)	1
Influenza	4/21 (19%)	6	0/52 (0%)	0	0/2 (0%)	0	0/5 (0%)	0
Nasopharyngitis	3/21 (14.3%)	5	4/52 (7.7%)	5	0/2 (0%)	0	0/5 (0%)	0
Upper respiratory tract infection	0/21 (0%)	0	0/52 (0%)	0	0/2 (0%)	0	1/5 (20%)	3
Urinary tract infection	0/21 (0%)	0	0/52 (0%)	0	0/2 (0%)	0	1/5 (20%)	1
Injury, poisoning and procedural complications
Ligament sprain	0/21 (0%)	0	3/52 (5.8%)	5	0/2 (0%)	0	0/5 (0%)	0
Musculoskeletal and connective tissue disorders
Joint range of motion decreased	0/21 (0%)	0	0/52 (0%)	0	0/2 (0%)	0	1/5 (20%)	1
Muscle spasms	0/21 (0%)	0	0/52 (0%)	0	0/2 (0%)	0	1/5 (20%)	1
Nervous system disorders
Headache	2/21 (9.5%)	2	1/52 (1.9%)	2	0/2 (0%)	0	0/5 (0%)	0
Psychiatric disorders
Libido decreased	0/21 (0%)	0	0/52 (0%)	0	0/2 (0%)	0	1/5 (20%)	1
Respiratory, thoracic and mediastinal disorders
Cough	2/21 (9.5%)	2	1/52 (1.9%)	1	0/2 (0%)	0	1/5 (20%)	1
Skin and subcutaneous tissue disorders
Rash	0/21 (0%)	0	0/52 (0%)	0	0/2 (0%)	0	1/5 (20%)	1
Vascular disorders
Hypertension	0/21 (0%)	0	0/52 (0%)	0	0/2 (0%)	0	1/5 (20%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

At the end of the trial, one or more scientific publications may be prepared collaboratively by the investigator(s) and Novo Nordisk. Novo Nordisk reserves the right to postpone publication and/or communication for up to 60 days to protect intellectual property.