Evaluation of Safety and Efficacy, Including Pharmacokinetics, of NNC 0129-0000-1003 When Administered for Treatment and Prophylaxis of Bleeding in Subjects With Haemophilia A

Congenital Bleeding Disorder Clinical Trial

— pathfinder™2  

Official title:

A Multi-national Trial Evaluating Safety and Efficacy, Including Pharmacokinetics, of NNC 0129-0000-1003 When Administered for Treatment and Prophylaxis of Bleeding in Patients With Haemophilia A

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01480180
• Other study ID #: NN7088-3859
• Secondary ID: U1111-1119-74162
• Status: Completed
• Phase: Phase 3
• Start date: January 30, 2012
• Est. completion date: December 10, 2018

Study information

• Verified date: November 2020
• Source: Novo Nordisk A/S
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This trial is conducted globally. The aim of the trial is to evaluate the safety and efficacy, including pharmacokinetics (the exposure of the trial drug in the body) of NNC 0129-0000-1003 (N8-GP) in subjects with Haemophilia A.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 186
• Est. completion date: December 10, 2018
• Est. primary completion date: December 10, 2018
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 12 Years and older

Eligibility

Inclusion Criteria: - Male patients with severe congenital haemophilia A (FVIII activity below 1%, according to medical records) - Documented history of at least 150 EDs (exposure days) to other FVIII products - At least 12 years and body weight at least 35 kg (except for Croatia, France, Russia, Israel and the Netherlands where the lower age limit will be 18 years) Exclusion Criteria: - Previous participation in this trial defined as withdrawal after administration N8-GP - Any history of FVIII inhibitors - FVIII inhibitors above or equal to 0.6 BU/mL at screening - HIV (human immunodeficiency virus) positive, defined by medical records with CD4+ (T-lymphocyte subtype) count below or equal to 200/mcL or a viral load of more than 400000 copies/mL. If the data is not available in medical records within last 6 months, CD4+ will be measured at the screening visit - Congenital or acquired coagulation disorders other than haemophilia A - Previous significant thromboembolic events (e.g. myocardial infarction, cerebrovascular disease or deep venous thrombosis) as defined by available medical records - Platelet count below 50,000 platelets/mcL (laboratory value at the screening visit) - ALAT (alanine aminotransferase) above 3 times the upper limit of normal reference ranges at central laboratory - Creatinine level equal to or greater than 1.5 times above upper normal limit (according to central laboratory reference ranges) - Ongoing immune modulating or chemotherapeutic medication

Related Conditions & MeSH terms

• Blood Coagulation Disorders
• Congenital Bleeding Disorder
• Haemophilia A
• Hemophilia A
• Hemorrhage
• Hemostatic Disorders

Intervention

Drug:
• turoctocog alfa pegol
Administered i.v.

Locations

Country	Name	City	State
Australia	Novo Nordisk Investigational Site	Camperdown	New South Wales
Australia	Novo Nordisk Investigational Site	Parkville	Victoria
Australia	Novo Nordisk Investigational Site	South Brisbane	Queensland
Brazil	Novo Nordisk Investigational Site	Campinas	Sao Paulo
Bulgaria	Novo Nordisk Investigational Site	Sofia
Croatia	Novo Nordisk Investigational Site	Split
Croatia	Novo Nordisk Investigational Site	Zagreb
Denmark	Novo Nordisk Investigational Site	Århus N
Denmark	Novo Nordisk Investigational Site	København Ø
France	Novo Nordisk Investigational Site	Bron Cedex
France	Novo Nordisk Investigational Site	Kremlin-Bicêtre
France	Novo Nordisk Investigational Site	Nantes Cedex 1
France	Novo Nordisk Investigational Site	Paris
Germany	Novo Nordisk Investigational Site	Berlin
Germany	Novo Nordisk Investigational Site	Bonn
Germany	Novo Nordisk Investigational Site	Frankfurt/M.
Germany	Novo Nordisk Investigational Site	Hannover
Germany	Novo Nordisk Investigational Site	Homburg
Germany	Novo Nordisk Investigational Site	München
Hungary	Novo Nordisk Investigational Site	Budapest
Hungary	Novo Nordisk Investigational Site	Debrecen
Israel	Novo Nordisk Investigational Site	Tel-Hashomer
Italy	Novo Nordisk Investigational Site	Firenze
Italy	Novo Nordisk Investigational Site	Milano
Italy	Novo Nordisk Investigational Site	Udine
Italy	Novo Nordisk Investigational Site	Vicenza
Japan	Novo Nordisk Investigational Site	Aichi
Japan	Novo Nordisk Investigational Site	Hiroshima
Japan	Novo Nordisk Investigational Site	Kitakyusyu, Fukuoka
Japan	Novo Nordisk Investigational Site	Nara
Japan	Novo Nordisk Investigational Site	Saitama
Japan	Novo Nordisk Investigational Site	Shimotsuke-shi, Tochigi
Japan	Novo Nordisk Investigational Site	Shizuoka
Japan	Novo Nordisk Investigational Site	Tokyo
Japan	Novo Nordisk Investigational Site	Tokyo
Japan	Novo Nordisk Investigational Site	Tokyo
Japan	Novo Nordisk Investigational Site	Yokohama-shi, Kanagawa
Korea, Republic of	Novo Nordisk Investigational Site	Daejeon
Malaysia	Novo Nordisk Investigational Site	Kuala Lumpur
Malaysia	Novo Nordisk Investigational Site	Selangor Darul Ehsan
Netherlands	Novo Nordisk Investigational Site	Groningen
Netherlands	Novo Nordisk Investigational Site	Rotterdam
Norway	Novo Nordisk Investigational Site	Oslo
Puerto Rico	Novo Nordisk Investigational Site	San Juan
Russian Federation	Novo Nordisk Investigational Site	Saint-Petersburg
Spain	Novo Nordisk Investigational Site	Madrid
Spain	Novo Nordisk Investigational Site	Málaga
Sweden	Novo Nordisk Investigational Site	Malmö
Switzerland	Novo Nordisk Investigational Site	Genève 14
Switzerland	Novo Nordisk Investigational Site	Lausanne
Switzerland	Novo Nordisk Investigational Site	Zürich
Taiwan	Novo Nordisk Investigational Site	Changhua
Taiwan	Novo Nordisk Investigational Site	Taipei
Turkey	Novo Nordisk Investigational Site	Adana
Turkey	Novo Nordisk Investigational Site	Bornova-IZMIR
Turkey	Novo Nordisk Investigational Site	Samsun
United Kingdom	Novo Nordisk Investigational Site	Basingstoke
United Kingdom	Novo Nordisk Investigational Site	Cardiff
United Kingdom	Novo Nordisk Investigational Site	London
United Kingdom	Novo Nordisk Investigational Site	London
United Kingdom	Novo Nordisk Investigational Site	Oxford
United Kingdom	Novo Nordisk Investigational Site	Sheffield
United States	Novo Nordisk Investigational Site	Augusta	Georgia
United States	Novo Nordisk Investigational Site	Baltimore	Maryland
United States	Novo Nordisk Investigational Site	Boise	Idaho
United States	Novo Nordisk Investigational Site	Boston	Massachusetts
United States	Novo Nordisk Investigational Site	Charleston	South Carolina
United States	Novo Nordisk Investigational Site	Charlottesville	Virginia
United States	Novo Nordisk Investigational Site	Cincinnati	Ohio
United States	Novo Nordisk Investigational Site	Dayton	Ohio
United States	Novo Nordisk Investigational Site	Detroit	Michigan
United States	Novo Nordisk Investigational Site	East Lansing	Michigan
United States	Novo Nordisk Investigational Site	Houston	Texas
United States	Novo Nordisk Investigational Site	Iowa City	Iowa
United States	Novo Nordisk Investigational Site	Long Beach	California
United States	Novo Nordisk Investigational Site	Minneapolis	Minnesota
United States	Novo Nordisk Investigational Site	Nashville	Tennessee
United States	Novo Nordisk Investigational Site	New Brunswick	New Jersey
United States	Novo Nordisk Investigational Site	New Orleans	Louisiana
United States	Novo Nordisk Investigational Site	Newark	New Jersey
United States	Novo Nordisk Investigational Site	Norfolk	Virginia
United States	Novo Nordisk Investigational Site	Omaha	Nebraska
United States	Novo Nordisk Investigational Site	Orlando	Florida
United States	Novo Nordisk Investigational Site	Philadelphia	Pennsylvania
United States	Novo Nordisk Investigational Site	Philadelphia	Pennsylvania
United States	Novo Nordisk Investigational Site	Phoenix	Arizona
United States	Novo Nordisk Investigational Site	Portland	Oregon
United States	Novo Nordisk Investigational Site	Sacramento	California
United States	Novo Nordisk Investigational Site	Spokane	Washington
United States	Novo Nordisk Investigational Site	Tampa	Florida
United States	Novo Nordisk Investigational Site	Torrance	California
United States	Novo Nordisk Investigational Site	Washington	District of Columbia
United States	Novo Nordisk Investigational Site	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Novo Nordisk A/S

Countries where clinical trial is conducted

United States,  Australia,  Brazil,  Bulgaria,  Croatia,  Denmark,  France,  Germany,  Hungary,  Israel,  Italy,  Japan,  Korea, Republic of,  Malaysia,  Netherlands,  Norway,  Puerto Rico,  Russian Federation,  Spain,  Sweden,  Switzerland,  Taiwan,  Turkey,  United Kingdom, 

References & Publications (3)

Giangrande P, Abdul Karim F, Nemes L, You CW, Landorph A, Geybels MS, Curry N. Long-term safety and efficacy of N8-GP in previously treated adults and adolescents with hemophilia A: Final results from pathfinder2. J Thromb Haemost. 2020 Sep;18 Suppl 1:5-1 — View Citation

Giangrande P, Andreeva T, Chowdary P, Ehrenforth S, Hanabusa H, Leebeek FW, Lentz SR, Nemes L, Poulsen LH, Santagostino E, You CW, Clausen WH, Jönsson PG, Oldenburg J; Pathfinder™2 Investigators. Clinical evaluation of glycoPEGylated recombinant FVIII: Ef — View Citation

Giangrande P, Chowdary P, Enhrenforth S, Hanabusa H, Leebeek FW, Lentz SR, Nemes L, Poulsen LH, Santagostino E, You CW, Clausen WHO, Oldenburg J and on behalf of for the pathfinder™2 Investigators. Clinical evaluation of novel recombinant glycopegylated F

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The Incidence Rate of FVIII-inhibitors =0.6 BU: After Approximately 19 Months	All participants with neutralizing antibodies were included in the numerator and any participant with a minimum 50 exposure days plus any participant with inhibitory inhibitors was included in the denominator. A positive inhibitor test was defined as =0.6 bethesda unit (BU). Estimates are based on exact calculations for a binomial distribution. For the calculation of the 'inhibitor rate' the nominator included all participants with neutralising antibodies while the denominator included all participants with a minimum of 50 exposures plus any participant with less than 50 exposures but with neutralising inhibitors.	After approximately 19 months
Primary	Annualised Bleeding Rate in the Prophylaxis Arm: After Approximately 19 Months	Annualised bleeding rate (ABR) is the number of bleeding episodes per year. This was assessed only for the prophylaxis treatment with N8-GP.	After approximately 19 months
Primary	The Incidence Rate of FVIII-inhibitors =0.6 BU: After Approximately 25 Months	All participants with neutralizing antibodies were included in the numerator and any participant with a minimum 50 exposure days plus any participant with inhibitory inhibitors was included in the denominator. A positive inhibitor test was defined as =0.6 bethesda unit (BU). Estimates are based on exact calculations for a binomial distribution. For the calculation of the 'inhibitor rate' the nominator included all participants with neutralising antibodies while the denominator included all participants with a minimum of 50 exposures plus any participant with less than 50 exposures but with neutralising inhibitors.	After approximately 25 months
Primary	Annualised Bleeding Rate in the Prophylaxis Arm: After Approximately 25 Months	ABR is the number of bleeding episodes per year. This was assessed only for the prophylaxis treatment with N8-GP.	After approximately 25 months
Primary	Incidence Rate of FVIII-inhibitors =0.6 BU: At Approximately 80 Months	All participants with neutralizing antibodies were included in the numerator and any participant with a minimum 50 exposure days plus any participant with inhibitory inhibitors was included in the denominator. A positive inhibitor test was defined as =0.6 bethesda unit (BU). Estimates are based on exact calculations for a binomial distribution. For the calculation of the 'inhibitor rate' the nominator included all participants with neutralising antibodies while the denominator included all participants with a minimum of 50 exposures plus any participant with less than 50 exposures but with neutralising inhibitors.	At approximately 80 months
Primary	Annualised Bleeding Rate in the Prophylaxis Arm: After Approximately 80 Months	Annualised bleeding rate (ABR) is the number of bleeding episodes per year reported during the prophylactic treatment with N8-GP.	After approximately 80 months
Secondary	Haemostatic Effect of N8-GP When Used for Treatment of Bleeds, Assessed on a Four-point Scale for Haemostatic Response (Excellent, Good, Moderate and None): After Approximately 19 Months	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 participant and/or parent(s)/caregiver within approximately 8 hours after a single injection as follows: Excellent: Abrupt pain relief and/or clear improvement in objective signs of bleeding within approximately 8 hrs after a single injection; Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8 hrs 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.	After approximately 19 months
Secondary	Haemostatic Effect of N8-GP When Used for Treatment of Bleeds, Assessed on a Four-point Scale for Haemostatic Response (Excellent, Good, Moderate and None): After Approximately 25 Months	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 participant and/or parent(s)/caregiver within approximately 8 hours after a single injection as follows: Excellent: Abrupt pain relief and/or clear improvement in objective signs of bleeding within approximately 8 hrs after a single injection; Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8 hrs 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.	After approximately 25 months
Secondary	Haemostatic Effect of N8-GP When Used for Treatment of Bleeds, Assessed on a Four-point Scale for Haemostatic Response (Excellent, Good, Moderate and None): After Approximately 80 Months	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 participant and/or parent(s)/caregiver within approximately 8 hours after a single injection as follows: Excellent: Abrupt pain relief and/or clear improvement in objective signs of bleeding within approximately 8 hrs after a single injection; Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8 hrs 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.	After approximately 80 months
Secondary	Consumption of N8-GP Per Bleeding Episode (Number of Infusions): After Approximately 19 Months	The mean number of infusions of N8-GP used for treatment of a bleed from start to stop of a bleed was reported.	After approximately 19 months
Secondary	Consumption of N8-GP Per Bleeding Episode (Number of Infusions): After Approximately 25 Months	The mean number of infusions of N8-GP used for treatment of a bleed from start to stop of a bleed was reported.	After approximately 25 months
Secondary	Consumption of N8-GP Per Bleeding Episode (Number of Infusions): After Approximately 80 Months	The mean number of infusions of N8-GP used for treatment of a bleed from start to stop of a bleed was reported.	After approximately 80 months
Secondary	Consumption of N8-GP Per Bleeding Episode (U/kg): After Approximately 19 Months	The mean consumption of N8-GP (U/kg) used for treatment of a bleed from start to stop of a bleed was reported.	After approximately 19 months
Secondary	Consumption of N8-GP Per Bleeding Episode (U/kg): After Approximately 25 Months	The mean consumption of N8-GP (U/kg) used for treatment of a bleed from start to stop of a bleed was reported.	After approximately 25 months
Secondary	Consumption of N8-GP Per Bleeding Episode (U/kg): After Approximately 80 Months	The mean consumption of N8-GP (U/kg) used for treatment of a bleed from start to stop of a bleed was reported.	After approximately 80 months
Secondary	Consumption of N8-GP (Number of Infusions) During Prophylaxis and On-demand Treatment: After Approximately 19 Months	Number of infusions are presented as average dose used during propphylaxis and on-demand treatment.	After approximately 19 months
Secondary	Consumption of N8-GP (Number of Infusions) During Prophylaxis and On-demand Treatment: After Approximately 25 Months	Number of infusions are presented as average dose used during prophylaxis and on-demand treatment.	After approximately 25 months
Secondary	Consumption of N8-GP (Number of Infusions) During Prophylaxis and On-demand Treatment: After Approximately 80 Months	Number of infusions are presented as average dose used during prophylaxis and on-demand treatment.	After approximately 80 months
Secondary	Consumption of N8-GP (U/kg Per Month) During Prophylaxis and On-demand Treatment: After Approximately 19 Months	The mean consumption of N8-GP used for treatment of a bleed from start to stop of a bleed (per month per participant) was reported.	After approximately 19 months
Secondary	Consumption of N8-GP (U/kg Per Month) During Prophylaxis and On-demand Treatment: After Approximately 25 Months	The mean consumption of N8-GP used for treatment of a bleed from start to stop of a bleed (per month per participant) was reported.	After approximately 25 months
Secondary	Consumption of N8-GP (U/kg Per Month) During Prophylaxis and On-demand Treatment: After Approximately 80 Months	The mean consumption of N8-GP used for treatment of a bleed from start to stop of a bleed (per month per participant) was reported.	After approximately 80 months
Secondary	Consumption of N8-GP (U/kg Per Year) During Prophylaxis and On-demand Treatment: After Approximately 19 Months	The mean consumption of N8-GP used for treatment of a bleed from start to stop of a bleed (per year per participant) was reported.	After approximately 19 months
Secondary	Consumption of N8-GP (U/kg Per Year) During Prophylaxis and On-demand Treatment: After Approximately 25 Months	The mean consumption of N8-GP used for treatment of a bleed from start to stop of a bleed (per year per participant) was reported.	After approximately 25 months
Secondary	Consumption of N8-GP (U/kg Per Year) During Prophylaxis and On-demand Treatment: After Approximately 80 Months	The mean consumption of N8-GP used for treatment of a bleed from start to stop of a bleed (per year per participant) was reported.	After approximately 80 months
Secondary	Haemostatic Effect as Measured by Recovery and Trough Levels FVIII:C (in All Patients Receiving Prophylaxis Treatment): After Approximately 19 Months	Recovery and trough levels of FVIII:C was reported for all participants at Visit 3 (Week 4) and end of main phase (approx. 19 months). The data was reported for all participants who received prophylaxis treatment. Chromogenic assay was performed with N8-GP product specific standard (PSS) as a calibrator.	After approximately 19 months
Secondary	Haemostatic Effect as Measured by Recovery and Trough Levels FVIII:C (in All Patients Receiving Prophylaxis Treatment): After Approximately 25 Months	Recovery and trough levels of FVIII:C was reported for all participants at the end of extension phase 1 study (approx. 25 months). The data was reported for all participants who received prophylaxis treatment. Chromogenic assay was performed with N8-GP product specific standard (PSS) as a calibrator.	After approximately 25 months
Secondary	Haemostatic Effect as Measured by Recovery and Trough Levels FVIII:C (in All Patients Receiving Prophylaxis Treatment): After Approximately 80 Months	Since patients were allowed to change prophylaxis regimen at any time during the extension phase part 2, and since the visit intervals were different for the 2 prophylaxis treatment regimens (Q4D and Q7D), FVIII activity data are reported only as incremental recovery at this timepoint.	After approximately 80 months
Secondary	Patient Reported Outcomes - Change in HAEMO-QOL Total Scores (Patients 13-16 Years Old) After Approx 19 and 25 Months	Reported results are change from baseline (Month 0) measured at end of main phase (approx Month 19) and change from Month 19 at end of Extension 1 (approx Month 25) of the study. The HAEMO-QOL assessment included questions on physical health, feeling, view of yourself, family, friends, perceived support, other persons, sports and school, dealing with haemophilia, treatment, future, and relationships. Scores range for each question was 0-100, with a lower score indicating better quality of life related to haemophilia.	After approx 19 and 25 months
Secondary	Patient Reported Outcomes - Change in HAEMO-QOL Total Scores (Patients 13-16 Years Old): After Approx 80 Months	Reported results are change from visit 1 (Month 0) upto end of Extension phase 2 (Month 80) of the study. Time intervals are assigned based on time after first dose. It was possible that a participant could answer more than one questionnaire in a single time interval. The HAEMO-QOL assessment included questions on physical health, feeling, view of yourself, family, friends, perceived support, other persons, sports and school, dealing with haemophilia, treatment, future, and relationships. Scores range for each question was 0-100, with a lower score indicating better quality of life related to haemophilia. Overall number of units analysed = Maximum no of questionnaires answered by participants for this endpoint. Overall number of participants analysed = maximum number of participants contributed to the analysis for each time point.	2-<3 yrs, 3-<4 yrs, 4-<5 yrs, 5-<6 yrs and 6-<7 yrs
Secondary	Patient Reported Outcomes - Change in HAEMO-QOL Total Scores (Parents of Patients 13-16 Years Old): After Approx 19 and 25 Months	Reported results are change from baseline (Month 0) measured at end of main phase (Month 19) and change from Month 19 to end of Extension 1 (Month 25) of the study. The questionnaire was completed by parents of the patients in the 13-16 years old age bracket. The HAEMO-QOL assessment included questions on physical health, feeling, view of yourself, family, friends, perceived support, other persons, sports and school, dealing with haemophilia, treatment, future, and relationships. Scores range for each question was 0-100, with a lower score indicating better quality of life related to haemophilia.	After approx 19 and 25 months
Secondary	Patient Reported Outcomes - Change in HAEMO-QOL Total Scores (Parents of Patients 13-16 Years Old): After Approx 80 Months	Reported results are change from visit 1 (Month 0) upto end of Extension phase 2 (Month 80) of the study. The questionnaire was completed by parents of the patients in the 13-16 years old age bracket. Time intervals are assigned based on time after first dose. It was possible that a participant could answer more than one questionnaire in a single time interval. The HAEMO-QOL assessment included questions on physical health, feeling, view of yourself, family, friends, perceived support, other persons, sports and school, dealing with haemophilia, treatment, future, and relationships. Scores range for each question was 0-100, with a lower score indicating better quality of life related to haemophilia. Overall number of units analysed = Maximum no of questionnaires answered by participants for this endpoint. Overall number of participants analysed = maximum number of participants contributed to the analysis for each time point.	2-<3 yrs, 3-<4 yrs, 4-<5 yrs, 5-<6 yrs and 6-<7 yrs
Secondary	Patient Reported Outcomes - Change in HAEM-A-QOL (>=17 Years) Total Scores: After Approx 19 and 25 Months	Reported results are change from baseline (Month 0) measured at end of main phase (Month 19) and change from Month 19 to end of Extension 1 (Month 25) of the study. The HAEM-A-QOL (for adults (>=17 years)) assessment included questions on questions on physical health, feeling, view of yourself, sports and leisure, work and school, dealing with haemophilia, treatment, future, family planning, and partnership and sexuality. Scores range for each question was 0-100, with a lower score indicating better quality of life related to haemophilia.	After approx 19 and 25 months
Secondary	Patient Reported Outcomes - Change in HAEM-A-QOL (>=17 Years) Total Scores: After Approximately 80 Months	Reported results are change from visit 1 (Month 0) upto end of Extension phase 2 (Month 80) of the study. Time intervals are assigned based on time after first dose. It was possible that a participant could answer more than one questionnaire in a single time interval. Overall number of units analysed = Maximum no of questionnaires answered by participants for this endpoint. Overall number of participants analysed = maximum number of participants contributed to the analysis for each time point. The HAEM-A-QOL (for adults (>=17 years)) assessment included questions on physical health, feeling, view of yourself, sports and leisure, work and school, dealing with haemophilia, treatment, future, family planning, and partnership and sexuality. Scores range for each question was 0-100, with a lower score indicating better quality of life related to haemophilia. Scores range for each question was 0-100, with a lower score indicating better quality of life related to haemophilia.	2-<3 yrs, 3-<4 yrs, 4-<5 yrs, 5-<6 yrs and 6-<7 yrs
Secondary	Patient Reported Outcomes - Change in HEMO-SAT (Patients) Scores: After Approx 19 and 25 Months	Reported results are change from baseline (Month 0) measured at end of main phase (Month 19) and change from Month 19 to end of Extension 1 (Month 25) of the study. The HEMO-SAT (Hematology-satisfaction) assessment included questions on treatment aspects including Ease and convenience, efficacy, burden, specialist/nurses, centre/hospital, general satisfaction (reported by patients). Adults completing the questionnaire could achieve a score from 0 to 100, with lower scores reflecting greater treatment satisfaction. The scale range for each of the 6 domains was 0-100 with lower scores reflecting greater treatment satisfaction. A decrease in the score would mean improvement.	After approx 19 and 25 months
Secondary	Patient Reported Outcomes - Change in HEMO-SAT (Patients) Scores: After Approximately 80 Months	Reported results are change from visit 1 (Month 0) upto end of Extension phase 2 (Month 80) of the study. Time intervals are assigned based on time after first dose. It was possible that a participant could answer more than one questionnaire in a single time interval. Overall number of units analysed = Maximum no of questionnaires answered by participants for this endpoint. Overall number of participants analysed = maximum number of participants contributed to the analysis for each time point. The HEMO-SAT assessment included questions on treatment aspects including Ease and convenience, efficacy, burden, specialist/nurses, centre/hospital, general satisfaction (reported by patients). Adults completing the questionnaire could achieve a score from 0 to 100, with lower scores reflecting greater treatment satisfaction. The scale range for each of the 6 domains was 0-100 with lower scores reflecting greater treatment satisfaction. A decrease in the score would mean improvement.	1-<2 yrs, 2-<3 yrs, 3-<4 yrs, 4-<5 yrs, 5-<6 yrs and 6-<7 yrs
Secondary	Patient Reported Outcomes - Change in HEMO-SAT Scores (Parents): After Approx 19 and 25 Months	The summary of change was based on individual changes observed at visit 13 (approximately 19 months) from visit 2a pre-dose (Month 0). The HEMO-SAT assessment included questions on treatment aspects including Ease and convenience, efficacy, burden, specialist/nurses, centre/hospital, general satisfaction (reported by parents). Adults completing the questionnaire could achieve a score from 0 to 100, with lower scores reflecting greater treatment satisfaction. The scale range for each of the 6 domains was 0-100 with lower scores reflecting greater treatment satisfaction. A decrease in the score would mean improvement.	After approx 19 and 25 months
Secondary	Patient Reported Outcomes - Change in HEMO-SAT (Parents) Scores: After Approximately 80 Months	Reported results are from Visit 1 (Month 0), and change from visit 1 upto end of Extension phase 2 (Month 80) of the study. Time intervals are assigned based on time after first dose. It was possible that a participant could answer more than one questionnaire in a single time interval. Overall number of units analysed = Max. no of questionnaires answered by participants for this endpoint. Overall number of participants analysed = max. number of participants contributed to the analysis for each time point. The HEMO-SAT assessment included questions on treatment aspects including Ease and convenience, efficacy, burden, specialist/nurses, centre/hospital, general satisfaction. Adults completing the questionnaire could achieve a score from 0 to 100, with lower scores reflecting greater treatment satisfaction. The scale range for each of the 6 domains was 0-100 with lower scores reflecting greater treatment satisfaction. A decrease in the score would mean improvement.	2-<3 yrs, 3-<4 yrs, 4-<5 yrs, 5-<6 yrs and 6-<7 yrs
Secondary	Patient Reported Outcomes - Change in EQ-5D-VAS Scores: After Approx 19 and 25 Months	Reported results are change from baseline (Month 0) measured at end of main phase (Month 19) and change from Month 19 to end of Extension 1 (Month 25) of the study. The European quality of life visual analogue scale (EQ5D-VAS) records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement. EQ-5D-VAS: range 0 to 100. A higher score indicates better self reported health status. A positive change indicates an improvement.	After approx 19 and 25 months
Secondary	Patient Reported Outcomes - Change in EQ-5D-VAS Scores: After Approximately 80 Months	Reported results are change from visit 1 (Month 0) upto end of Extension phase 2 (Month 80) of the study. Time intervals are assigned based on time after first dose. It was possible that a participant could answer more than one questionnaire in a single time interval. Overall number of units analysed = Maximum no of questionnaires answered by participants for this endpoint. Overall number of participants analysed = maximum number of participants contributed to the analysis for each time point. The EQ5D-VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement. EQ-5D-VAS: range 0 to 100. A higher score indicates better self reported health status. A positive change indicates an improvement.	1-<2 yrs, 2-<3 yrs, 3-<4 yrs, 4-<5 yrs, 5-<6 yrs and 6-<7 yrs
Secondary	Patient Reported Outcomes - Change in European Quality of Life Utility Index: After Approx 19 and 25 Months	Reported results are change from baseline (Month 0) measured at end of main phase (Month 19) and change from Month 19 to end of Extension 1 (Month 25) of the study. The European quality of life utility index comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 3 levels where 1 indicates better health state (no problems) and 3 indicates worst health state (confined to bed). Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range -0.594 to 1.000; a positive change indicates an improvement.	After approx 19 and 25 months
Secondary	Patient Reported Outcomes - Change in European Quality of Life Utility Index Scores: After Approximately 80 Months	Reported results are change from visit 1 (Month 0) upto end of Extension phase 2 (Month 80) of the study. Time intervals are assigned based on time after first dose. It is possible that a patient answers more than one questionnaire in a single time interval. Overall units analysed = Max no. of questionnaires answered by participants for this endpoint. Overall no. of participants analysed = max no. of participants analysed at each time point. This utility index has 5 dimensions: mobility, self-care, usual activities, pain/discomfort & anxiety/depression. Each dimension has 3 levels where 1 indicates better health state (no problems) and 3 indicates worst health state (confined to bed). Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and results in a total score range -0.594 to 1.000; a positive change indicates an improvement.	1-<2 yrs, 2-<3 yrs, 3-<4 yrs, 4-<5 yrs, 5-<6 yrs and 6-<7 yrs
Secondary	Number of Hospital Admissions During the Trial	The number of hospital admissions that took place in the study were reported.	After approx 19, 25 and 80 months
Secondary	Number of Days at the Hospital During the Trial	The mean number of days that participants spent at the hospital during the study were reported.	After approx 19, 25 and 80 months
Secondary	Number of Admissions to the Emergency Room (ER) During the Trial	The number of admissions to the ER that took place in the study were reported for each group.	After approx 19, 25 and 80 months
Secondary	Number of Days Missing School or Work	The mean number of days that participants missed to go to school or work were reported.	Approx 19, 25 and 80 months
Secondary	Number of Days Using Mobility Aid	The mean number of days that participants used any aids for mobility during the study were reported.	Approx 19, 25 and 80 months
Secondary	Number of Participants Using Pain Medication	The number of participants using pain medication during the main plus extension phase 1 of the study (approximately 25 months) and during extension phase 2(approximately 80 months) were reported.	After approx 25 and 80 months
Secondary	Number of Bleeds Using Pain Medication	The mean number of bleeds using pain medication in the main phase of the study (approximately 19 months) were reported.	After approx 19 months
Secondary	Number of Adverse Events Reported During the Trial Period: After Approximately 19 Months	All presented adverse events (AEs) are treatment-emergent. A treatment-emergent adverse event was defined as an event with onset after first N8-GP administration.	After approx 19 months
Secondary	Number of Adverse Events Reported During the Trial Period: After Approximately 25 Months	All presented adverse events (AEs) are treatment-emergent. A treatment-emergent adverse event was defined as an event with onset after first N8-GP administration.	After approx. 25 months
Secondary	Number of Adverse Events Reported During the Trial Period: After Approximately 80 Months	The number of adverse events observed during the study after approximately 80 months was reported.	After approximately 80 months
Secondary	Number of Serious Adverse Events Reported During the Trial Period: After Approximately 19 Months	All presented serious adverse events (SAEs) are treatment-emergent. A treatment-emergent adverse event was defined as an event with onset after first N8-GP administration.	After approximately 19 months
Secondary	Number of Serious Adverse Events Reported During the Trial Period: After Approximately 25 Months	All presented serious adverse events (SAEs) are treatment-emergent. A treatment-emergent adverse event was defined as an event with onset after first N8-GP administration.	After approximately 25 months
Secondary	Number of Serious Adverse Events Reported During the Trial Period: After Approximately 80 Months	All presented serious adverse events (SAEs) are treatment-emergent. A treatment-emergent adverse event was defined as an event with onset after first N8-GP administration.	After approximately 80 months
Secondary	Change in Blood Pressure: After Approximately 19 Months	The mean change in the systolic and diastolic blood pressure values of participants was reported. The summary of change was based on individual changes observed at visit 13 (approximately 19 months) from visit 2a pre-dose (Month 0).	After approximately 19 months
Secondary	Change in Blood Pressure: After Approximately 25 Months	The mean change in the systolic and diastolic blood pressure values of participants was reported. The summary of change was based on individual changes observed at visit 17 (approximately month 25) from visit 13 (approximately month 19).	After approximately 19 and 25 months
Secondary	Change in Blood Pressure: After Approximately 80 Months	Change in the blood pressure was not calculated in the extension phase 2 of the study since participants were allowed to change from Q4D to Q7D and vice versa.	After approximately 80 months
Secondary	Change in Pulse: After Approximately 19 Months	The mean change in the pulse values of participants was reported. The summary of change was based on individual changes observed at visit 13 (approximately 19 months) from visit 2a pre-dose (Month 0).	After approximately 19 months
Secondary	Change in Pulse: After Approximately 25 Months	The mean change in the pulse values of participants was reported. The summary of change was based on individual changes observed at visit 17 (approximately month 25) from visit 13 (approximately month 19).	After approximately 25 months
Secondary	Change in Pulse: After Approximately 80 Months	Change in pulse was not calculated in the extension phase 2 of the study since participants were allowed to change from Q4D to Q7D and vice versa.	After approximately 80 months
Secondary	Change in Body Temperature: After Approximately 19 Months	The mean change in the body temperature values of participants was reported. The summary of change was based on individual changes observed at visit 13 (approximately 19 months) from visit 2a pre-dose (Month 0).	After approximately 19 months
Secondary	Change in Body Temperature: After Approximately 25 Months	The mean change in the body temperature (C) values of participants was reported. The summary of change was based on individual changes observed at visit 17 (approximately month 25) from visit 13 (approximately month 19).	After approximately 25 months
Secondary	Change in Body Temperature: After Approximately 80 Months	Change in body temperature was not calculated in the extension phase 2 of the study since participants were allowed to change from Q4D to Q7D and vice versa.	After approximately 80 months
Secondary	Change in Respiratory Rate: After Approximately 19 Months	The mean change in the respiratory rate values of participants was reported. The summary of change was based on individual changes observed at visit 13 (approximately 19 months) from visit 2a pre-dose (Month 0).	After approximately 19 months
Secondary	Change in Respiratory Rate: After Approximately 25 Months	The mean change in the respiratory rate (breaths/min) values of participants was reported. The summary of change was based on individual changes observed at visit 17 (approximately month 25) from visit 13 (approximately month 19).	After approximately 25 months
Secondary	Change in Respiratory Rate: After Approximately 80 Months	Change in respiratory rate was not calculated in the extension phase 2 of the study since participants were allowed to change from Q4D to Q7D and vice versa.	After approximately 80 months
Secondary	FVIII Activity 30 Min Post -Injection (C30min)	FVIII plasma activity was measured after 30 mins of injection. This was measured at two time points Visit 2a (Week 0) and visit 7 (Week 28) during the Main Phase of the study. Chromogenic assay was performed with normal human plasma (NHP) as a calibrator	Week 0, week 28
Secondary	Incremental Recovery (Single Dose and Steady State)	Incremental recovery was defined as the dose-normalised activity recorded 30 min after end of injection. This was measured at two time points Visit 2a (Week 0) and visit 7 (Week 28) during the Main Phase of the study. Chromogenic assay was performed with normal human plasma (NHP) as a calibrator.	Week 0, week 28
Secondary	Trough Level (Single Dose and Steady State)	Trough level was defined as the plasma FVIII activity recorded immediately before next dose is given. This was measured at two time points Visit 2a (Week 0) and visit 7 (Week 28) during the Main Phase of the study. Chromogenic assay was performed with normal human plasma (NHP) as a calibrator.	Week 0, week 28
Secondary	Area Under the Curve (AUC0-inf)	Area under the plasma activity versus time profile from time zero to infinity (AUC0-inf) was measured at two time points Visit 2a (Week 0) and visit 7 (Week 28) during the Main Phase of the study. It is the measure of total plasma exposure. Chromogenic assay was performed with normal human plasma (NHP) as a calibrator.	Pre dose and 30 min, 1, 4, 12, 24, 48, 72 and 96 hours post dose at week 0 and week 28
Secondary	Area Under the Curve (AUC0-t)	Area under the plasma activity versus time profile from time zero to the last measurable activity (AUC0-t) was measured at two time points Visit 2a (Week 0) and visit 7 (Week 28) during the Main Phase of the study. Chromogenic assay was performed with normal human plasma (NHP) as a calibrator.	Pre dose and 30 min, 1, 4, 12, 24, 48, 72 and 96 hours post dose at week 0 and week 28
Secondary	Terminal Half Life (t1/2)	t½ = ln(2) / ?z, where ?z is the terminal elimination rate constant. The terminal elimination rate constant was estimated using linear regression on the terminal part of the log(activity) versus time profile. This was measured at Visit 2a (Week 0) and visit 7 (Week 28) during the Main Phase of the study. Chromogenic assay was performed with normal human plasma (NHP) as a calibrator.	Pre dose and 30 min, 1, 4, 12, 24, 48, 72 and 96 hours post dose at week 0 and week 28
Secondary	Clearance (CL)	Total plasma clearance (CL) of drug after intravenous administration was reported. Clearance was calculated using the formula CL= Dose / AUC(0-inf). This was measured at two time points Visit 2a (Week 0) and visit 7 (Week 28) during the Main Phase of the study. Chromogenic assay was performed with normal human plasma (NHP) as a calibrator.	Pre dose and 30 min, 1, 4, 12, 24, 48, 72 and 96 hours post dose at week 0 and week 28
Secondary	Mean Residence Time (MRT)	MRT = AUMC/AUC(0-inf), where AUMC is the area under the first moment curve, i.e. the area under the curve t·C(t), calculated with the same method as AUC(0-inf) (linear trapezoidal method + extrapolated area). This was measured at two time points Visit 2a (Week 0) and visit 7 (Week 28) during the Main Phase of the study. Chromogenic assay was performed with normal human plasma (NHP) as a calibrator.	Pre dose and 30 min, 1, 4, 12, 24, 48, 72 and 96 hours post dose at week 0 and week 28
Secondary	Volume of Distribution at Steady State (Vss)	Apparent volume of distribution at steady state is a product of the mean residence time and clearance and was calculated using the formula - Vss = CL x MRT. This was measured at two time points Visit 2a (Week 0) and visit 7 (Week 28) during the Main Phase of the study. Chromogenic assay was performed with normal human plasma (NHP) as a calibrator.	Pre dose and 30 min, 1, 4, 12, 24, 48, 72 and 96 hours post dose at week 0 and week 28

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