pathfinder™5: A Multinational, Open-Label, Non-Controlled Trial on Safety, Efficacy and Pharmacokinetics of NNC 0129-0000-1003 in Previously Treated Paediatric Patients With Severe Haemophilia A

• Sponsor: Novo Nordisk A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01731600
• Collaborator: (none)
• Enrollment: 68
• Locations: 51
• Arm: 1
• Actual Duration (Months): 67.2
• Patients Per Site: 1.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This trial is conducted globally. The aim of the trial is to investigate safety, efficacy and pharmacokinetics (the exposure of the trial drug in the body) of NNC 0129-0000-1003 (N8-GP) in children with severe haemophilia A who have undergone treatment with previous factor VIII (FVIII) products.

Condition or Disease	Intervention/Treatment	Phase
Congenital Bleeding Disorder; Haemophilia A	Drug: turoctocog alfa pegol	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 68 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multinational, Open-Label, Non-Controlled Trial on Safety, Efficacy and Pharmacokinetics of NNC 0129-0000-1003 in Previously Treated Paediatric Patients With Severe Haemophilia A
• Actual Study Start Date: Feb 20, 2013
• Actual Primary Completion Date: Sep 15, 2014
• Actual Study Completion Date: Sep 28, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: N8-GP	Drug: turoctocog alfa pegol; Fixed dose of turoctocog alfa pegol for intravenous injections (i.v.) twice weekly for prophylaxis. In addition, turoctocog alfa pegol will be administered to treat bleeding episodes during the trial period. Bleeding episodes will be treated with doses of 20-75 U/kg body weight.; Other Names: NNC 0129-0000-1003 N8-GP

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Inhibitory Antibodies Against Coagulation Factor VIII (FVIII) ≥0.6 Bethesda Units [During the main phase of the trial (from 0-26 weeks of treatment)]

   The number of participants with inhibitory antibodies against coagulation factor VIII (FVIII) ≥0.6 Bethesda units was presented.

Secondary Outcome Measures

1. Frequency of Adverse Events Including Serious Adverse Events Reported During the Trial Period [Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)]

   The frequency of adverse events including serious adverse events reported during the main and extension phase of the trial. The data presented is the rate of AE i.e. number of AEs per patient years of exposue.

2. Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None [Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)]

   Haemostatic effect of N8-GP for treatment of bleeding episodes was assessed by 4-point response scale: none, moderate, good or excellent. Evaluation during trial was done by patient and/or parent(s)/caregiver 8 hours after first injection as follows: Excellent: Abrupt pain relief and/or clear improvement in objective signs of bleeding within approximately 8 hours after a single injection; Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8 hours after a single injection, but possibly requiring more than one injection for complete resolution; Moderate: Probable or slight beneficial effect within approximately 8 hours after the first injection, but usually requiring more than one injection; None: No improvement, or worsening of symptoms.

3. Number of Bleeding Episodes During Prophylactic Treatment With N8-GP (Annualised Bleeding Rate) [Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)]

   The number of bleeding episodes per year reported during the prophylactic treatment with N8-GP.

4. Consumption of N8-GP Per Bleeding Episode (Number of Injections) [Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)]

   The mean number of injections of N8-GP used for treatment of a bleed from start to stop of a bleed.

5. Consumption of N8-GP Per Bleeding Episode (U/kg) [Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)]

   The mean consumption of N8-GP used for treatment of a bleed from start to stop of a bleed.

6. Consumption of N8-GP During Prophylaxis (Number of Injections) [Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)]

   The mean number of injections of N8-GP used for treatment of a bleed from start to stop of a bleed during prophylaxis.

7. Consumption of N8-GP During Prophylaxis (U/kg Per Month) [Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)]

   The mean consumption of N8-GP used for treatment of a bleed from start to stop of a bleed during prophylaxis (per month per subject). Consumption used for treatment includes all doses given (prophylaxis, treatment of bleed, minor surgery and pharmacokinetics [PK])

8. Consumption of N8-GP During Prophylaxis (U/kg Per Year) [Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)]

   The mean consumption of N8-GP used for treatment of a bleed from start to stop of a bleed during prophylaxis (per year per subject). Consumption used for treatment includes all doses given (prophylaxis, treatment of bleed, minor surgery and pharmacokinetics)

9. Incremental Recovery (Defined as the Peak Level Recorded 60 Min After End of Injection) Evaluated for Previous FVIII Product [2-6 weeks prior to initial dosing with N8-GP and up to 30 hours after administration of previous FVIII product]

   The incremental recovery was defined as the increase in plasma FVIII activity per IU/kg of factor administered recorded 60 minutes after end of injection. It was calculated as (Factor VIII procoagulant [FVIII:C] activity measured in plasma 60 min after dosing - FVIII:C activity measured in plasma immediately before dosing) / (dose injected at time 0 min), where the dose was expressed as U FVIII product per kg body weight. A chromogenic assay with normal human plasma (NHP) as calibrator was used.

10. Incremental Recovery (Defined as the Peak Level Recorded 60 Min After End of Injection) Evaluated for N8-GP [From 1 hour prior to and up to 96 hours after initial administration of N8-GP]

    The incremental recovery was defined as the peak level recorded 60 min after end of injection and dose-normalised. It was calculated as (FVIII:C activity measured in plasma 60 min after dosing - FVIII:C activity measured in plasma immediately before dosing) / (dose injected at time 0 min), where the dose was expressed as U FVIII product per kg body weight. A chromogenic assay with product specific calibrator (PSS) as calibrator was used.

11. Area Under the Curve Evaluated for Previous FVIII Product [2-6 weeks prior to initial dosing with N8-GP and up to 30 hours after administration of previous FVIII product]

    Area under the curve (AUC) versus time from zero to infinity. This is calculated as AUC = AUClast + (C(t) / λz), where C(t) is the last measurable concentration. A chromogenic assay with NHP as calibrator was used.

12. Area Under the Curve Evaluated for N8-GP [From 1 hour prior to and up to 96 hours after initial administration of N8-GP]

    Area under the curve versus time from zero to infinity. This is calculated as AUC = AUClast + (C(t) / λz), where C(t) is the last measurable concentration. A chromogenic assay with product specific standard (PSS) as calibrator was used.

13. Terminal Half-life Evaluated for Previous FVIII Product [2-6 weeks prior to initial dosing with N8-GP and up to 30 hours after administration of previous FVIII product]

    t½ = ln(2) / λz, where t½ is terminal half-life and λz is the terminal elimination rate. The terminal elimination rate was planned estimated using linear regression on the terminal part of the time versus log(concentration) curve. A population-based method simultaneously estimating individual t½ values for all patients was applied, including patients with few values above the lower limit of quantification (LLOQ). This was estimated using time points from 1h to 30h. A chromogenic assay with PSS as calibrator was used.

14. Terminal Half-life Evaluated for N8-GP [From 1 hour prior to and up to 96 hours after initial administration of N8-GP]

    t½ = ln(2) / λz, where λz is the terminal elimination rate. The terminal elimination rate was planned estimated using linear regression on the terminal part of the time versus log(concentration) curve. A population-based method simultaneously estimating individual t½ values for all patients was applied, including patients with few values above the LLOQ. This was estimated using time points from 6h to 96h. A chromogenic assay with PSS as calibrator was used.

15. Clearance Evaluated for Previous FVIII Product [2-6 weeks prior to initial dosing with N8-GP and up to 30 hours after administration of previous FVIII product]

    Total plasma clearance of drug after intravenous administration measured as actual dose/AUC. A chromogenic assay with NHP as calibrator was used.

16. Clearance Evaluated for N8-GP [From 1 hour prior to and up to 96 hours after initial administration of N8-GP.]

    Total plasma clearance of drug after intravenous administration measured as actual dose/AUC. A chromogenic assay with PSS as calibrator was used.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 0 Years to 11 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male patients with severe congenital haemophilia A (FVIII activity level below 1%)

• Weight above or equal to 10 kg - Documented history of 150 exposure days (ED) to FVIII products for patients aged 6-11 years and above 50 ED to FVIII products for patients aged 0-5 years

Exclusion Criteria:

• Any history of FVIII inhibitors

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novo Nordisk Investigational Site	Phoenix	Arizona	United States	85016-7710
2	Novo Nordisk Investigational Site	Long Beach	California	United States	90806
3	Novo Nordisk Investigational Site	Orange	California	United States	92868
4	Novo Nordisk Investigational Site	Washington	District of Columbia	United States	20010-2978
5	Novo Nordisk Investigational Site	Orlando	Florida	United States	32827
6	Novo Nordisk Investigational Site	Tampa	Florida	United States	33607
7	Novo Nordisk Investigational Site	Boise	Idaho	United States	83712
8	Novo Nordisk Investigational Site	Iowa City	Iowa	United States	52242
9	Novo Nordisk Investigational Site	New Orleans	Louisiana	United States	70118-5720
10	Novo Nordisk Investigational Site	Boston	Massachusetts	United States	02115
11	Novo Nordisk Investigational Site	Minneapolis	Minnesota	United States	55404
12	Novo Nordisk Investigational Site	Omaha	Nebraska	United States	68198-6828
13	Novo Nordisk Investigational Site	New Hyde Park	New York	United States	11040
14	Novo Nordisk Investigational Site	Charlotte	North Carolina	United States	28204
15	Novo Nordisk Investigational Site	Cincinnati	Ohio	United States	45229
16	Novo Nordisk Investigational Site	Dayton	Ohio	United States	45404
17	Novo Nordisk Investigational Site	Philadelphia	Pennsylvania	United States	19104
18	Novo Nordisk Investigational Site	Philadelphia	Pennsylvania	United States	19134
19	Novo Nordisk Investigational Site	Charleston	South Carolina	United States	29425
20	Novo Nordisk Investigational Site	Nashville	Tennessee	United States	37232-9830
21	Novo Nordisk Investigational Site	Dallas	Texas	United States	75235
22	Novo Nordisk Investigational Site	Houston	Texas	United States	77030
23	Novo Nordisk Investigational Site	Charlottesville	Virginia	United States	22903
24	Novo Nordisk Investigational Site	Spokane	Washington	United States	99204
25	Novo Nordisk Investigational Site	Rio de Janeiro		Brazil	20211-030
26	Novo Nordisk Investigational Site	Toronto	Ontario	Canada	M5G 1X8
27	Novo Nordisk Investigational Site	Bron Cedex		France	69677
28	Novo Nordisk Investigational Site	Lille		France	59097
29	Novo Nordisk Investigational Site	Paris		France	75015
30	Novo Nordisk Investigational Site	Athens		Greece	GR-11527
31	Novo Nordisk Investigational Site	Thessaloniki		Greece	GR 54642
32	Novo Nordisk Investigational Site	Tel-Hashomer		Israel	52621
33	Novo Nordisk Investigational Site	Vicenza		Italy	36100
34	Novo Nordisk Investigational Site	Kitakyusyu, Fukuoka		Japan	807 8555
35	Novo Nordisk Investigational Site	Tokyo		Japan	167-0035
36	Novo Nordisk Investigational Site	Vilnius		Lithuania	LT-08406
37	Novo Nordisk Investigational Site	Kuala Lumpur		Malaysia	50400
38	Novo Nordisk Investigational Site	Porto		Portugal	4200-319
39	Novo Nordisk Investigational Site	San Juan		Puerto Rico	00935
40	Novo Nordisk Investigational Site	Bellinzona		Switzerland	6500
41	Novo Nordisk Investigational Site	Luzern 16		Switzerland	6000
42	Novo Nordisk Investigational Site	Zürich		Switzerland	8032
43	Novo Nordisk Investigational Site	Antalya		Turkey	01010
44	Novo Nordisk Investigational Site	Bornova-IZMIR		Turkey	35100
45	Novo Nordisk Investigational Site	Izmit		Turkey	41380
46	Novo Nordisk Investigational Site	Samsun		Turkey
47	Novo Nordisk Investigational Site	Donetsk		Ukraine	83045
48	Novo Nordisk Investigational Site	Lviv		Ukraine	79044
49	Novo Nordisk Investigational Site	Leicester		United Kingdom	LE1 5WW
50	Novo Nordisk Investigational Site	London		United Kingdom	SE1 7EH
51	Novo Nordisk Investigational Site	Oxford		United Kingdom	OX3 9DU

Sponsors and Collaborators

• Novo Nordisk A/S

Investigators

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

Study Documents (Full-Text)

• Study Protocol - Nov 13, 2015

More Information

Additional Information:

• Clinical Trials at Novo Nordisk

Publications

None provided.

• Responsible Party: Novo Nordisk A/S
• ClinicalTrials.gov Identifier: NCT01731600
• Other Study ID Numbers: NN7088-3885; U1111-1129-6009; 2012-001711-23; JapicCTI-132214
• First Posted: Nov 22, 2012
• Last Update Posted: Nov 23, 2020
• Last Verified: Nov 1, 2020

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

Study Results

Participant Flow

Recruitment Details	The trial was conducted at 36 sites in 15 countries as follows: Canada (1), France (2), Germany (1), Greece (2 sites screened/1 site randomised subjects), Israel (1), Italy (1), Japan (2), Lithuania (1), Malaysia (1), Portugal (1), Switzerland (3), Turkey (3), Ukraine (2), United Kingdom (3), and United States (12).

Arm/Group Title	Younger Children (0 - 5 Years)	Older Children (6 - 11 Years)
Arm/Group Description	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). Prophylaxis: N8-GP as a single bolus iv injection 60 IU/kg twice weekly. Treatment of bleeding episodes: N8-GP ranging from 20-75 IU/kg, according to severity and location of bleeding episode. The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). Prophylaxis: N8-GP as a single bolus iv injection 60 IU/kg twice weekly. Treatment of bleeding episodes: N8-GP ranging from 20-75 IU/kg, according to severity and location of bleeding episode. The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.
Period Title: Overall Study
STARTED	34	34
COMPLETED	28	34
NOT COMPLETED	6	0

Baseline Characteristics

Arm/Group Title	Younger Children (0 - 5 Years)	Older Children (6 - 11 Years)	Total
Arm/Group Description	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). Prophylaxis: N8-GP as a single bolus iv injection 60 IU/kg twice weekly. Treatment of bleeding episodes: N8-GP ranging from 20-75 IU/kg, according to severity and location of bleeding episode. The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). Prophylaxis: N8-GP as a single bolus iv injection 60 IU/kg twice weekly. Treatment of bleeding episodes: N8-GP ranging from 20-75 IU/kg, according to severity and location of bleeding episode. The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.	Total of all reporting groups
Overall Participants	34	34	68
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	3.0 (1.3)	8.9 (1.7)	6.0 (3.3)
Age, Customized (Count of Participants)
Infants and toddlers (28 days-23 months)	6 17.6%	0 0%	6 8.8%
Children (2-11 years)	28 82.4%	34 100%	62 91.2%
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	34 100%	34 100%	68 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	3 8.8%	3 4.4%
Not Hispanic or Latino	34 100%	30 88.2%	64 94.1%
Unknown or Not Reported	0 0%	1 2.9%	1 1.5%
Race/Ethnicity, Customized (Count of Participants)
White	30 88.2%	25 73.5%	55 80.9%
Black or African American	2 5.9%	1 2.9%	3 4.4%
Asian	1 2.9%	4 11.8%	5 7.4%
Other	1 2.9%	1 2.9%	2 2.9%
Not applicable	0 0%	3 8.8%	3 4.4%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Inhibitory Antibodies Against Coagulation Factor VIII (FVIII) ≥0.6 Bethesda Units
Description	The number of participants with inhibitory antibodies against coagulation factor VIII (FVIII) ≥0.6 Bethesda units was presented.
Time Frame	During the main phase of the trial (from 0-26 weeks of treatment)

Outcome Measure Data

Analysis Population Description

Results were based on safety analysis set (SAS). The SAS consists of all patients exposed to at least one dose of turoctocog alfa pegol. Number analysed = participants with minimum of 50 exposure days and developed inhibitory antibodies

Arm/Group Title	Younger Children (0 - 5 Years) [Main Trial]	Older Children (6 - 11 Years) [Main Trial]
Arm/Group Description	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days).	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days).
Measure Participants	34	34
Number [Participants]	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Younger Children (0 - 5 Years) [Main Trial], Older Children (6 - 11 Years) [Main Trial]
	Comments	A one-sided, upper 97.5% confidence limit was provided based on an exact calculation in the binomial distribution.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Incidence rate
	Estimated Value	0
	Confidence Interval	(1-Sided) 97.5%; to 0.067
	Parameter Dispersion	Type: Value:
	Estimation Comments	The incidence of inhibitory antibodies was calculated as number of patients with inhibitors during the main phase of the trial divided by number of patients in the main phase of the trial.

2. Secondary Outcome

Title	Frequency of Adverse Events Including Serious Adverse Events Reported During the Trial Period
Description	The frequency of adverse events including serious adverse events reported during the main and extension phase of the trial. The data presented is the rate of AE i.e. number of AEs per patient years of exposue.
Time Frame	Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)

Outcome Measure Data

Analysis Population Description

Results were based on SAS.

Arm/Group Title	Younger Children (0 - 5 Years) [Main Trial]	Older Children (6 - 11 Years) [Main Trial]	Younger Children (0 - 5 Years) [Full Trial]	Older Children (6 - 11 Years) [Full Trial]
Arm/Group Description	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days).	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days).	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.
Measure Participants	34	34	34	34
Number [Events per patient years of exposure]	4.87	4.74	3.09	2.45

3. Secondary Outcome

Title	Haemostatic Effect of N8-GP When Used for Treatment of Bleeding Episodes and Assessed as: Excellent, Good, Moderate, or None
Description	Haemostatic effect of N8-GP for treatment of bleeding episodes was assessed by 4-point response scale: none, moderate, good or excellent. Evaluation during trial was done by patient and/or parent(s)/caregiver 8 hours after first injection as follows: Excellent: Abrupt pain relief and/or clear improvement in objective signs of bleeding within approximately 8 hours after a single injection; Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8 hours after a single injection, but possibly requiring more than one injection for complete resolution; Moderate: Probable or slight beneficial effect within approximately 8 hours after the first injection, but usually requiring more than one injection; None: No improvement, or worsening of symptoms.
Time Frame	Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)

Outcome Measure Data

Analysis Population Description

Results were based on full analysis set (FAS). All trial patients allocated to treatment, for which at least one of the pharmacokinetic or efficacy endpoints was assessed, were included in the FAS.

Arm/Group Title	Younger Children (0 - 5 Years) [Main Trial]	Older Children (6 - 11 Years) [Main Trial]	Younger Children (0 - 5 Years) [Full Trial]	Older Children (6 - 11 Years) [Full Trial]
Arm/Group Description	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days).	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days).	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.
Measure Participants	34	34	34	34
Measure Bleeding episodes	30	40	108	222
Excellent	11	12	47	96
Good	13	19	48	74
Moderate	4	7	9	44
None	1	0	2	2
Missing	1	2	2	6

4. Secondary Outcome

Title	Number of Bleeding Episodes During Prophylactic Treatment With N8-GP (Annualised Bleeding Rate)
Description	The number of bleeding episodes per year reported during the prophylactic treatment with N8-GP.
Time Frame	Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)

Outcome Measure Data

Analysis Population Description

Results were based on FAS.

Arm/Group Title	Younger Children (0 - 5 Years) [Main Trial]	Older Children (6 - 11 Years) [Main Trial]	Younger Children (0 - 5 Years) [Full Trial]	Older Children (6 - 11 Years) [Full Trial]
Arm/Group Description	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days).	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days).	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.
Measure Participants	34	34	34	34
Median (Inter-Quartile Range) [bleeds/patient/year]	1.94	1.97	0.61	0.93

5. Secondary Outcome

Title	Consumption of N8-GP Per Bleeding Episode (Number of Injections)
Description	The mean number of injections of N8-GP used for treatment of a bleed from start to stop of a bleed.
Time Frame	Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)

Outcome Measure Data

Analysis Population Description

Results were based on FAS.

Arm/Group Title	Younger Children (0 - 5 Years) [Main Trial]	Older Children (6 - 11 Years) [Main Trial]	Younger Children (0 - 5 Years) [Full Trial]	Older Children (6 - 11 Years) [Full Trial]
Arm/Group Description	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days).	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days).	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.
Measure Participants	34	34	34	34
Measure Bleeding episodes	30	40	108	222
Mean (Standard Deviation) [Number of injections]	1.9 (1.5)	1.6 (0.9)	1.6 (1.3)	1.5 (1.1)

6. Secondary Outcome

Title	Consumption of N8-GP Per Bleeding Episode (U/kg)
Description	The mean consumption of N8-GP used for treatment of a bleed from start to stop of a bleed.
Time Frame	Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)

Outcome Measure Data

Analysis Population Description

Results were based on FAS.

Arm/Group Title	Younger Children (0 - 5 Years) [Main Trial]	Older Children (6 - 11 Years) [Main Trial]	Younger Children (0 - 5 Years) [Full Trial]	Older Children (6 - 11 Years) [Full Trial]
Arm/Group Description	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days).	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days).	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.
Measure Participants	34	34	40	34
Measure Bleeding episodes	30	40	108	222
Mean (Standard Deviation) [IU/kg/bleed]	123 (104.9)	99 (54.4)	102.8 (81)	91 (58.3)

7. Secondary Outcome

Title	Consumption of N8-GP During Prophylaxis (Number of Injections)
Description	The mean number of injections of N8-GP used for treatment of a bleed from start to stop of a bleed during prophylaxis.
Time Frame	Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)

Outcome Measure Data

Analysis Population Description

Results were based on FAS.

Arm/Group Title	Younger Children (0 - 5 Years) [Main Trial]	Older Children (6 - 11 Years) [Main Trial]	Younger Children (0 - 5 Years) [Full Trial]	Older Children (6 - 11 Years) [Full Trial]
Arm/Group Description	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days).	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days).	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.
Measure Participants	34	34	34	34
Measure Injections	1592	1799	14442	17243
Mean (Standard Deviation) [Number of injections]	65.3 (6.5)	62.3 (7.4)	65.4 (7.5)	64.1 (5.3)

8. Secondary Outcome

Title	Consumption of N8-GP During Prophylaxis (U/kg Per Month)
Description	The mean consumption of N8-GP used for treatment of a bleed from start to stop of a bleed during prophylaxis (per month per subject). Consumption used for treatment includes all doses given (prophylaxis, treatment of bleed, minor surgery and pharmacokinetics [PK])
Time Frame	Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)

Outcome Measure Data

Analysis Population Description

Results were based on FAS.

Arm/Group Title	Younger Children (0 - 5 Years) [Main Trial]	Older Children (6 - 11 Years) [Main Trial]	Younger Children (0 - 5 Years) [Full Trial]	Older Children (6 - 11 Years) [Full Trial]
Arm/Group Description	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days).	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days).	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.
Measure Participants	34	34	34	34
Mean (Standard Deviation) [U/kg/month]	572.5 (97.4)	555.8 (44.6)	564.9 (86.6)	563.4 (15.1)

9. Secondary Outcome

Title	Consumption of N8-GP During Prophylaxis (U/kg Per Year)
Description	The mean consumption of N8-GP used for treatment of a bleed from start to stop of a bleed during prophylaxis (per year per subject). Consumption used for treatment includes all doses given (prophylaxis, treatment of bleed, minor surgery and pharmacokinetics)
Time Frame	Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient's completion of the trial, an average of 4.5 years)

Outcome Measure Data

Analysis Population Description

Results were based on FAS.

Arm/Group Title	Younger Children (0 - 5 Years) [Main Trial]	Older Children (6 - 11 Years) [Main Trial]	Younger Children (0 - 5 Years) [Full Trial]	Older Children (6 - 11 Years) [Full Trial]
Arm/Group Description	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days).	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days).	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.
Measure Participants	34	34	34	34
Mean (Standard Deviation) [U/kg/year]	6870.3 (1169)	6669.6 (535.8)	6778.6 (1039)	6760.4 (181.8)

10. Secondary Outcome

Title	Incremental Recovery (Defined as the Peak Level Recorded 60 Min After End of Injection) Evaluated for Previous FVIII Product
Description	The incremental recovery was defined as the increase in plasma FVIII activity per IU/kg of factor administered recorded 60 minutes after end of injection. It was calculated as (Factor VIII procoagulant [FVIII:C] activity measured in plasma 60 min after dosing - FVIII:C activity measured in plasma immediately before dosing) / (dose injected at time 0 min), where the dose was expressed as U FVIII product per kg body weight. A chromogenic assay with normal human plasma (NHP) as calibrator was used.
Time Frame	2-6 weeks prior to initial dosing with N8-GP and up to 30 hours after administration of previous FVIII product

Outcome Measure Data

Analysis Population Description

Results were based on FAS.

Arm/Group Title	Younger Children (0 - 5 Years) [Full Trial]	Older Children (6 - 11 Years) [Full Trial]
Arm/Group Description	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.
Measure Participants	34	34
Least Squares Mean (95% Confidence Interval) [(IU/mL)/(U/kg)]	0.017	0.022

11. Secondary Outcome

Title	Incremental Recovery (Defined as the Peak Level Recorded 60 Min After End of Injection) Evaluated for N8-GP
Description	The incremental recovery was defined as the peak level recorded 60 min after end of injection and dose-normalised. It was calculated as (FVIII:C activity measured in plasma 60 min after dosing - FVIII:C activity measured in plasma immediately before dosing) / (dose injected at time 0 min), where the dose was expressed as U FVIII product per kg body weight. A chromogenic assay with product specific calibrator (PSS) as calibrator was used.
Time Frame	From 1 hour prior to and up to 96 hours after initial administration of N8-GP

Outcome Measure Data

Analysis Population Description

Results were based on FAS.

Arm/Group Title	Younger Children (0 - 5 Years) [Full Trial]	Older Children (6 - 11 Years) [Full Trial]
Arm/Group Description	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.
Measure Participants	34	34
Least Squares Mean (95% Confidence Interval) [(IU/mL)/(U/kg)]	0.018	0.020

12. Secondary Outcome

Title	Area Under the Curve Evaluated for Previous FVIII Product
Description	Area under the curve (AUC) versus time from zero to infinity. This is calculated as AUC = AUClast + (C(t) / λz), where C(t) is the last measurable concentration. A chromogenic assay with NHP as calibrator was used.
Time Frame	2-6 weeks prior to initial dosing with N8-GP and up to 30 hours after administration of previous FVIII product

Outcome Measure Data

Analysis Population Description

Results were based on FAS

Arm/Group Title	Younger Children (0 - 5 Years) [Full Trial]	Older Children (6 - 11 Years) [Full Trial]
Arm/Group Description	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.
Measure Participants	34	34
Least Squares Mean (95% Confidence Interval) [IU×h/mL]	11.628	12.203

13. Secondary Outcome

Title	Area Under the Curve Evaluated for N8-GP
Description	Area under the curve versus time from zero to infinity. This is calculated as AUC = AUClast + (C(t) / λz), where C(t) is the last measurable concentration. A chromogenic assay with product specific standard (PSS) as calibrator was used.
Time Frame	From 1 hour prior to and up to 96 hours after initial administration of N8-GP

Outcome Measure Data

Analysis Population Description

Results were based on FAS.

Arm/Group Title	Younger Children (0 - 5 Years) [Full Trial]	Older Children (6 - 11 Years) [Full Trial]
Arm/Group Description	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.
Measure Participants	34	34
Least Squares Mean (95% Confidence Interval) [IU*h/mL]	21.489	25.026

14. Secondary Outcome

Title	Terminal Half-life Evaluated for Previous FVIII Product
Description	t½ = ln(2) / λz, where t½ is terminal half-life and λz is the terminal elimination rate. The terminal elimination rate was planned estimated using linear regression on the terminal part of the time versus log(concentration) curve. A population-based method simultaneously estimating individual t½ values for all patients was applied, including patients with few values above the lower limit of quantification (LLOQ). This was estimated using time points from 1h to 30h. A chromogenic assay with PSS as calibrator was used.
Time Frame	2-6 weeks prior to initial dosing with N8-GP and up to 30 hours after administration of previous FVIII product

Outcome Measure Data

Analysis Population Description

Results were based on FAS.

Arm/Group Title	Younger Children (0 - 5 Years) [Full Trial]	Older Children (6 - 11 Years) [Full Trial]
Arm/Group Description	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.
Measure Participants	34	34
Geometric Mean (Geometric Coefficient of Variation) [hours]	7.2 (20.1)	7.5 (19.1)

15. Secondary Outcome

Title	Terminal Half-life Evaluated for N8-GP
Description	t½ = ln(2) / λz, where λz is the terminal elimination rate. The terminal elimination rate was planned estimated using linear regression on the terminal part of the time versus log(concentration) curve. A population-based method simultaneously estimating individual t½ values for all patients was applied, including patients with few values above the LLOQ. This was estimated using time points from 6h to 96h. A chromogenic assay with PSS as calibrator was used.
Time Frame	From 1 hour prior to and up to 96 hours after initial administration of N8-GP

Outcome Measure Data

Analysis Population Description

Results were based on FAS.

Arm/Group Title	Younger Children (0 - 5 Years) [Full Trial]	Older Children (6 - 11 Years) [Full Trial]
Arm/Group Description	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.
Measure Participants	34	34
Geometric Mean (Geometric Coefficient of Variation) [hours]	13.6 (20.4)	14.1 (25.0)

16. Secondary Outcome

Title	Clearance Evaluated for Previous FVIII Product
Description	Total plasma clearance of drug after intravenous administration measured as actual dose/AUC. A chromogenic assay with NHP as calibrator was used.
Time Frame	2-6 weeks prior to initial dosing with N8-GP and up to 30 hours after administration of previous FVIII product

Outcome Measure Data

Analysis Population Description

Results were based on FAS.

Arm/Group Title	Younger Children (0 - 5 Years) [Full Trial]	Older Children (6 - 11 Years) [Full Trial]
Arm/Group Description	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.
Measure Participants	34	34
Least Squares Mean (95% Confidence Interval) [mL/h/kg]	4.322	3.867

17. Secondary Outcome

Title	Clearance Evaluated for N8-GP
Description	Total plasma clearance of drug after intravenous administration measured as actual dose/AUC. A chromogenic assay with PSS as calibrator was used.
Time Frame	From 1 hour prior to and up to 96 hours after initial administration of N8-GP.

Outcome Measure Data

Analysis Population Description

Results were based on FAS.

Arm/Group Title	Younger Children (0 - 5 Years) [Full Trial]	Older Children (6 - 11 Years) [Full Trial]
Arm/Group Description	Participants (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.	Participants (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.
Measure Participants	34	34
Least Squares Mean (95% Confidence Interval) [mL/h/kg]	2.601	2.386

Adverse Events

Time Frame	From first exposure to N8-GP (visit 2) of main phase to end of extension phase (>=4 days after last dose of N8-GP, up to 4.5 years).
Adverse Event Reporting Description	The safety analysis set consists of all patients exposed to at least one dose of N8-GP.
Arm/Group Title	Younger Children£(0-5 Years)		Older Children£(6-11 Years)
Arm/Group Description
All Cause Mortality
	Younger Children£(0-5 Years)		Older Children£(6-11 Years)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/34 (0%)		0/34 (0%)
Serious Adverse Events
	Younger Children£(0-5 Years)		Older Children£(6-11 Years)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/34 (32.4%)		5/34 (14.7%)
Gastrointestinal disorders
Abdominal hernia	0/34 (0%)	0	1/34 (2.9%)	1
Gastritis	0/34 (0%)	0	1/34 (2.9%)	1
General disorders
Pyrexia	1/34 (2.9%)	1	0/34 (0%)	0
Immune system disorders
Hypersensitivity	1/34 (2.9%)	1	0/34 (0%)	0
Infections and infestations
Cellulitis	1/34 (2.9%)	1	0/34 (0%)	0
Device related infection	1/34 (2.9%)	2	0/34 (0%)	0
Encephalitis	1/34 (2.9%)	1	0/34 (0%)	0
Sepsis syndrome	1/34 (2.9%)	1	0/34 (0%)	0
Tonsillitis	0/34 (0%)	0	1/34 (2.9%)	1
Injury, poisoning and procedural complications
Fall	1/34 (2.9%)	1	0/34 (0%)	0
Hand fracture	1/34 (2.9%)	1	0/34 (0%)	0
Head injury	0/34 (0%)	0	1/34 (2.9%)	1
Musculoskeletal and connective tissue disorders
Muscle haemorrhage	1/34 (2.9%)	1	0/34 (0%)	0
Reproductive system and breast disorders
Acquired phimosis	1/34 (2.9%)	1	0/34 (0%)	0
Respiratory, thoracic and mediastinal disorders
Adenoidal hypertrophy	0/34 (0%)	0	1/34 (2.9%)	1
Asthma	1/34 (2.9%)	1	0/34 (0%)	0
Vascular disorders
Haemorrhage	1/34 (2.9%)	1	0/34 (0%)	0
Other (Not Including Serious) Adverse Events
	Younger Children£(0-5 Years)		Older Children£(6-11 Years)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	33/34 (97.1%)		33/34 (97.1%)
Blood and lymphatic system disorders
Anaemia	2/34 (5.9%)	2	1/34 (2.9%)	1
Ear and labyrinth disorders
Cerumen impaction	2/34 (5.9%)	2	0/34 (0%)	0
Ear pain	4/34 (11.8%)	5	1/34 (2.9%)	2
Eye disorders
Conjunctivitis allergic	0/34 (0%)	0	3/34 (8.8%)	4
Gastrointestinal disorders
Abdominal pain	5/34 (14.7%)	7	2/34 (5.9%)	2
Chapped lips	0/34 (0%)	0	2/34 (5.9%)	2
Constipation	2/34 (5.9%)	2	3/34 (8.8%)	5
Dental caries	3/34 (8.8%)	5	1/34 (2.9%)	1
Diarrhoea	5/34 (14.7%)	7	4/34 (11.8%)	5
Nausea	0/34 (0%)	0	2/34 (5.9%)	2
Vomiting	9/34 (26.5%)	10	3/34 (8.8%)	7
General disorders
Hyperthermia	2/34 (5.9%)	2	1/34 (2.9%)	1
Peripheral swelling	0/34 (0%)	0	3/34 (8.8%)	3
Pyrexia	7/34 (20.6%)	16	6/34 (17.6%)	9
Immune system disorders
Food allergy	1/34 (2.9%)	2	2/34 (5.9%)	4
Seasonal allergy	2/34 (5.9%)	2	2/34 (5.9%)	2
Infections and infestations
Acute sinusitis	0/34 (0%)	0	2/34 (5.9%)	2
Bronchitis	3/34 (8.8%)	5	3/34 (8.8%)	3
Conjunctivitis	2/34 (5.9%)	2	2/34 (5.9%)	2
Ear infection	5/34 (14.7%)	5	3/34 (8.8%)	5
Gastroenteritis	7/34 (20.6%)	10	9/34 (26.5%)	13
Gastroenteritis viral	0/34 (0%)	0	2/34 (5.9%)	2
Influenza	5/34 (14.7%)	9	6/34 (17.6%)	10
Molluscum contagiosum	2/34 (5.9%)	2	1/34 (2.9%)	1
Nasopharyngitis	11/34 (32.4%)	21	10/34 (29.4%)	16
Otitis media	4/34 (11.8%)	4	5/34 (14.7%)	5
Pharyngitis	2/34 (5.9%)	2	1/34 (2.9%)	2
Pharyngitis streptococcal	2/34 (5.9%)	2	1/34 (2.9%)	2
Pharyngotonsillitis	0/34 (0%)	0	2/34 (5.9%)	2
Pneumonia	1/34 (2.9%)	1	2/34 (5.9%)	2
Rhinitis	8/34 (23.5%)	8	4/34 (11.8%)	7
Sinusitis	1/34 (2.9%)	1	2/34 (5.9%)	2
Tonsillitis	2/34 (5.9%)	2	2/34 (5.9%)	5
Upper respiratory tract infection	10/34 (29.4%)	20	13/34 (38.2%)	31
Varicella	6/34 (17.6%)	6	1/34 (2.9%)	1
Viral infection	4/34 (11.8%)	5	3/34 (8.8%)	3
Viral pharyngitis	2/34 (5.9%)	2	0/34 (0%)	0
Viral upper respiratory tract infection	4/34 (11.8%)	5	3/34 (8.8%)	5
Injury, poisoning and procedural complications
Arthropod bite	1/34 (2.9%)	2	2/34 (5.9%)	2
Arthropod sting	1/34 (2.9%)	3	3/34 (8.8%)	3
Contusion	4/34 (11.8%)	4	4/34 (11.8%)	4
Face injury	1/34 (2.9%)	1	2/34 (5.9%)	3
Fall	5/34 (14.7%)	8	3/34 (8.8%)	4
Head injury	3/34 (8.8%)	4	4/34 (11.8%)	5
Joint injury	2/34 (5.9%)	2	3/34 (8.8%)	4
Laceration	2/34 (5.9%)	2	4/34 (11.8%)	4
Ligament sprain	0/34 (0%)	0	5/34 (14.7%)	6
Limb injury	5/34 (14.7%)	5	4/34 (11.8%)	12
Skin abrasion	2/34 (5.9%)	2	3/34 (8.8%)	4
Musculoskeletal and connective tissue disorders
Arthralgia	3/34 (8.8%)	4	4/34 (11.8%)	5
Joint swelling	3/34 (8.8%)	3	0/34 (0%)	0
Pain in extremity	5/34 (14.7%)	11	6/34 (17.6%)	8
Tendonitis	0/34 (0%)	0	2/34 (5.9%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Skin papilloma	2/34 (5.9%)	2	0/34 (0%)	0
Nervous system disorders
Headache	5/34 (14.7%)	6	9/34 (26.5%)	16
Psychiatric disorders
Attention deficit/hyperactivity disorder	3/34 (8.8%)	3	1/34 (2.9%)	1
Reproductive system and breast disorders
Penile adhesion	2/34 (5.9%)	2	0/34 (0%)	0
Respiratory, thoracic and mediastinal disorders
Asthma	2/34 (5.9%)	4	1/34 (2.9%)	1
Cough	14/34 (41.2%)	26	6/34 (17.6%)	6
Epistaxis	4/34 (11.8%)	28	1/34 (2.9%)	3
Nasal congestion	2/34 (5.9%)	3	2/34 (5.9%)	2
Oropharyngeal pain	2/34 (5.9%)	2	8/34 (23.5%)	10
Rhinitis allergic	3/34 (8.8%)	3	1/34 (2.9%)	1
Rhinorrhoea	4/34 (11.8%)	4	3/34 (8.8%)	4
Skin and subcutaneous tissue disorders
Acne	0/34 (0%)	0	4/34 (11.8%)	5
Dermatitis	0/34 (0%)	0	2/34 (5.9%)	3
Dermatitis contact	1/34 (2.9%)	1	2/34 (5.9%)	2
Eczema	2/34 (5.9%)	2	5/34 (14.7%)	5
Erythema	3/34 (8.8%)	5	1/34 (2.9%)	1
Rash	7/34 (20.6%)	11	0/34 (0%)	0
Rash pruritic	0/34 (0%)	0	2/34 (5.9%)	2
Skin lesion	1/34 (2.9%)	1	2/34 (5.9%)	2
Urticaria	1/34 (2.9%)	1	2/34 (5.9%)	2
Vascular disorders
Haematoma	2/34 (5.9%)	2	0/34 (0%)	0

Limitations/Caveats

[Not Specified]

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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