Trial Outcomes & Findings for Safety and Efficacy of Turoctocog Alfa (N8) in Prevention and On-demand Treatment of Bleeding Episodes in Subjects With Haemophilia A: An Extension to Trials NN7008-3543, NN7008-3545, NN7008-3600, NN7008-3893 and NN7008-4015 (NCT NCT00984126)

Last Updated: 2017-07-27

Results Overview

The frequency of inhibitors was calculated as number of patients with inhibitors during the trial divided by number of patients in the trial. This endpoint was measured during the trial.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

214 participants

Primary outcome timeframe

After 90 months

Results posted on

2017-07-27

Participant Flow

The subjects were enrolled at 52 sites in 19 countries:Brazil (4 sites), Croatia (2), Germany (3), Israel (1), Italy (2), Japan (5), Latvia (1), Lithuania (1), Macedonia (1), Malaysia (1), Poland (2), Russian Federation (2), Serbia (5), Spain (2), Switzerland (1), Taiwan (1), Turkey (5), the United Kingdom (1) and the United States (12).

Subjects completing 1 of the trials NN7008-3543 (NCT00840086),NN7008-3545 (NCT01138501),NN7008-3600 (NCT01238367),NN7008-3893 (NCT01365520) and NN7008-4015 (NCT01692925) could continue treatment with turoctocog alfa in the extension trial (NN7008-3568). Both new subjects and those from main trial (NN7008-3568) could enter the on-demand sub-trial.

Participant milestones

Participant milestones
Measure	Small Children (0 - <6 Years) Subjects (0-\<6 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during the trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day,20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in the relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in the relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016)	Older Children (6 - <12 Years) Subjects (6-\<12 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day, 20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016).	Adolescents (12 - <18 Years) Subjects (12-\<18 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive regimen: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day, 20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly.On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016).	Adults (≥18 Years) Subjects (≥18 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive regimen: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day,20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016).
Overall Study STARTED	27	28	23	135
Overall Study COMPLETED	20	20	16	76
Overall Study NOT COMPLETED	7	8	7	59

Reasons for withdrawal

Reasons for withdrawal
Measure	Small Children (0 - <6 Years) Subjects (0-\<6 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during the trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day,20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in the relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in the relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016)	Older Children (6 - <12 Years) Subjects (6-\<12 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day, 20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016).	Adolescents (12 - <18 Years) Subjects (12-\<18 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive regimen: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day, 20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly.On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016).	Adults (≥18 Years) Subjects (≥18 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive regimen: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day,20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016).
Overall Study Protocol Violation	0	0	1	2
Overall Study Adverse Event	0	0	0	2
Overall Study Choose to join Pathfinder trial™ + other	7	7	3	46
Overall Study Withdrawal criteria	0	1	3	9

Baseline Characteristics

Safety and Efficacy of Turoctocog Alfa (N8) in Prevention and On-demand Treatment of Bleeding Episodes in Subjects With Haemophilia A: An Extension to Trials NN7008-3543, NN7008-3545, NN7008-3600, NN7008-3893 and NN7008-4015

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Small Children (0 - <6 Years) n=27 Participants Subjects (0-\<6 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during the trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day,20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in the relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in the relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016)	Older Children (6 - <12 Years) n=28 Participants Subjects (6-\<12 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day, 20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016).	Adolescents (12 - <18 Years) n=23 Participants Subjects (12-\<18 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive regimen: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day, 20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016).	Adults (≥18 Years) n=135 Participants Subjects (≥18 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive regimen: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day,20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016).	Total n=213 Participants Total of all reporting groups
Age, Continuous	4.6 years STANDARD_DEVIATION 1.4 • n=5 Participants	9.0 years STANDARD_DEVIATION 1.8 • n=7 Participants	14.9 years STANDARD_DEVIATION 1.7 • n=5 Participants	32.0 years STANDARD_DEVIATION 11.5 • n=4 Participants	23.6 years STANDARD_DEVIATION 14.6 • n=21 Participants
Age, Customized Small children (0 - <6 years)	27 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	0 participants n=4 Participants	27 participants n=21 Participants
Age, Customized Older children (6 - <12 Years)	0 participants n=5 Participants	28 participants n=7 Participants	0 participants n=5 Participants	0 participants n=4 Participants	28 participants n=21 Participants
Age, Customized Adolescents (12 - <18 Years)	0 participants n=5 Participants	0 participants n=7 Participants	23 participants n=5 Participants	0 participants n=4 Participants	23 participants n=21 Participants
Age, Customized Adults (≥18 Years)	0 participants n=5 Participants	0 participants n=7 Participants	0 participants n=5 Participants	135 participants n=4 Participants	135 participants n=21 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants
Sex: Female, Male Male	27 Participants n=5 Participants	28 Participants n=7 Participants	23 Participants n=5 Participants	135 Participants n=4 Participants	213 Participants n=21 Participants

PRIMARY outcome

Timeframe: After 90 months

Population: Full analysis set

The frequency of inhibitors was calculated as number of patients with inhibitors during the trial divided by number of patients in the trial. This endpoint was measured during the trial.

Outcome measures

Outcome measures
Measure	Small Children (0 - <6 Years) n=27 Participants Subjects (0-\<6 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during the trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day,20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in the relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in the relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016)	Older Children (6 - <12 Years) n=28 Participants Subjects (6-\<12 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day, 20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016).	Adolescents (12 - <18 Years) n=23 Participants Subjects (12-\<18 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive regimen: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day, 20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016).	Adults (≥18 Years) n=135 Participants Subjects (≥18 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive regimen: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day,20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016).	Adolescents (12-<18 Years)-(On-Demand Regimen [Main Trial]) Subjects (12-\<18 Years) in main trial received turoctocog alfa (on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. However during on-demand sub-trial, it was not possible for new subjects to switch to another regimen, subjects who did not comply with on-demand treatment regimen were to be withdrawn. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. Maximum treatment duration (27 Oct 2009-30 Jun 2016). On-Demand regimen: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment.	Adults (>=18 Years)-(On-Demand Regimen [Main Trial]) Subjects (≥18 Years) in main trial received turoctocog alfa (on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. However during on-demand sub-trial, it was not possible for new subjects to switch to another regimen, subjects who did not comply with on-demand treatment regimen were to be withdrawn. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. Maximum treatment duration (27 Oct 2009 - 30 Jun 2016). On-Demand regimen: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment.	Adults (>=18 Years)-(On-Demand Regimen [Sub-trial]) Subjects (≥18 Years) in sub-trial received turoctocog alfa (on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. However during on-demand sub-trial, it was not possible for new subjects to switch to another regimen, subjects who did not comply with on-demand treatment regimen were to be withdrawn. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. Maximum treatment duration (27 Oct 2009 - 30 Jun 2016). On-Demand regimen: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment.
Frequency of Development of FVIII Inhibitors (Greater Than or Equal to 0.6 Bethesda Units (BU)/mL)	0 subjects	0 subjects	0 subjects	0 subjects	—	—	—

SECONDARY outcome

Timeframe: After 90 months

Population: Safety Analysis Set includes all dosed subjects with data after dosing.

The number of adverse events and serious adverse events reported during the main trial and the on-demand sub-trial (during 90 months).

Outcome measures

Outcome measures
Measure	Small Children (0 - <6 Years) n=27 Participants Subjects (0-\<6 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during the trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day,20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in the relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in the relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016)	Older Children (6 - <12 Years) n=28 Participants Subjects (6-\<12 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day, 20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016).	Adolescents (12 - <18 Years) n=23 Participants Subjects (12-\<18 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive regimen: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day, 20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016).	Adults (≥18 Years) n=135 Participants Subjects (≥18 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive regimen: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day,20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016).	Adolescents (12-<18 Years)-(On-Demand Regimen [Main Trial]) Subjects (12-\<18 Years) in main trial received turoctocog alfa (on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. However during on-demand sub-trial, it was not possible for new subjects to switch to another regimen, subjects who did not comply with on-demand treatment regimen were to be withdrawn. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. Maximum treatment duration (27 Oct 2009-30 Jun 2016). On-Demand regimen: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment.	Adults (>=18 Years)-(On-Demand Regimen [Main Trial]) Subjects (≥18 Years) in main trial received turoctocog alfa (on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. However during on-demand sub-trial, it was not possible for new subjects to switch to another regimen, subjects who did not comply with on-demand treatment regimen were to be withdrawn. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. Maximum treatment duration (27 Oct 2009 - 30 Jun 2016). On-Demand regimen: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment.	Adults (>=18 Years)-(On-Demand Regimen [Sub-trial]) Subjects (≥18 Years) in sub-trial received turoctocog alfa (on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. However during on-demand sub-trial, it was not possible for new subjects to switch to another regimen, subjects who did not comply with on-demand treatment regimen were to be withdrawn. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. Maximum treatment duration (27 Oct 2009 - 30 Jun 2016). On-Demand regimen: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment.
Frequency of Adverse Events and Serious Adverse Events Adverse events	180 Number of Events	204 Number of Events	240 Number of Events	636 Number of Events	—	—	—
Frequency of Adverse Events and Serious Adverse Events Serious adverse events	6 Number of Events	8 Number of Events	6 Number of Events	27 Number of Events	—	—	—

SECONDARY outcome

Timeframe: After 90 months

Population: Full Analysis Set. Number of subjects analysed=Subjects who received preventive regimen and were evaluable for the outcome.

The number of bleeding episodes per year reported during the prevention period (during 90 months).

Outcome measures

Outcome measures
Measure	Small Children (0 - <6 Years) n=27 Participants Subjects (0-\<6 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during the trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day,20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in the relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in the relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016)	Older Children (6 - <12 Years) n=28 Participants Subjects (6-\<12 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day, 20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016).	Adolescents (12 - <18 Years) n=23 Participants Subjects (12-\<18 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive regimen: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day, 20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016).	Adults (≥18 Years) n=129 Participants Subjects (≥18 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive regimen: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day,20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016).	Adolescents (12-<18 Years)-(On-Demand Regimen [Main Trial]) Subjects (12-\<18 Years) in main trial received turoctocog alfa (on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. However during on-demand sub-trial, it was not possible for new subjects to switch to another regimen, subjects who did not comply with on-demand treatment regimen were to be withdrawn. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. Maximum treatment duration (27 Oct 2009-30 Jun 2016). On-Demand regimen: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment.	Adults (>=18 Years)-(On-Demand Regimen [Main Trial]) Subjects (≥18 Years) in main trial received turoctocog alfa (on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. However during on-demand sub-trial, it was not possible for new subjects to switch to another regimen, subjects who did not comply with on-demand treatment regimen were to be withdrawn. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. Maximum treatment duration (27 Oct 2009 - 30 Jun 2016). On-Demand regimen: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment.	Adults (>=18 Years)-(On-Demand Regimen [Sub-trial]) Subjects (≥18 Years) in sub-trial received turoctocog alfa (on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. However during on-demand sub-trial, it was not possible for new subjects to switch to another regimen, subjects who did not comply with on-demand treatment regimen were to be withdrawn. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. Maximum treatment duration (27 Oct 2009 - 30 Jun 2016). On-Demand regimen: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment.
Annualised Bleeding Rate Reported During the Prevention Period (Only Applicable for Subjects in the Preventive Regimen)	1.08 Bleeding episodes/year Interval 0.0 to 12.12	1.57 Bleeding episodes/year Interval 0.0 to 10.8	1.57 Bleeding episodes/year Interval 0.0 to 6.01	1.37 Bleeding episodes/year Interval 0.0 to 17.82	—	—	—

SECONDARY outcome

Timeframe: After 90 months

Population: Full Aanalysis Set. The endpoint was measured for preventive and on-demand regimen for comparison of the efficacy of turoctocog alfa between regimens. Number of subjects analysed=subjects who received preventive and on-demand regimen and were evaluable for this outcome.

Haemostatic response to turoctocog alfa (none, moderate, good or excellent) in treatment of bleeds using a four-point response scale: none, moderate, good or excellent. The evaluation was done by patient, caregiver and/or investigator based on experience as follows: 1. Excellent: Abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single infusion 2. Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8 hours after an infusion, but possibly requiring more than 1 infusion for complete resolution. 3. Moderate: Probable or slight beneficial effect within approximately 8 hours after the first infusion; usually requiring more than 1 infusion. 4. None: No improvement, or worsening of symptoms. This endpoint is measured during the preventive and on-demand sub-trial (during 90 months).

Outcome measures

Outcome measures
Measure	Small Children (0 - <6 Years) n=21 Participants Subjects (0-\<6 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during the trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day,20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in the relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in the relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016)	Older Children (6 - <12 Years) n=24 Participants Subjects (6-\<12 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day, 20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016).	Adolescents (12 - <18 Years) n=22 Participants Subjects (12-\<18 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive regimen: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day, 20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016).	Adults (≥18 Years) n=103 Participants Subjects (≥18 years) received turoctocog alfa (preventive or on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand regimen. Preventive regimen: turoctocog alfa as a slow iv bolus injection 20-50 IU/kg once every second day,20-60 IU/kg 3 times weekly or 40-60 IU/kg once every third day or twice weekly. On-Demand: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. The maximum treatment duration (27 Oct 2009 - 30 Jun 2016).	Adolescents (12-<18 Years)-(On-Demand Regimen [Main Trial]) n=1 Participants Subjects (12-\<18 Years) in main trial received turoctocog alfa (on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. However during on-demand sub-trial, it was not possible for new subjects to switch to another regimen, subjects who did not comply with on-demand treatment regimen were to be withdrawn. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. Maximum treatment duration (27 Oct 2009-30 Jun 2016). On-Demand regimen: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment.	Adults (>=18 Years)-(On-Demand Regimen [Main Trial]) n=7 Participants Subjects (≥18 Years) in main trial received turoctocog alfa (on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. However during on-demand sub-trial, it was not possible for new subjects to switch to another regimen, subjects who did not comply with on-demand treatment regimen were to be withdrawn. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. Maximum treatment duration (27 Oct 2009 - 30 Jun 2016). On-Demand regimen: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment.	Adults (>=18 Years)-(On-Demand Regimen [Sub-trial]) n=14 Participants Subjects (≥18 Years) in sub-trial received turoctocog alfa (on-demand regimen). Subjects switched between regimens during trial (main and on-demand sub-trial) upon investigators' discretion. However during on-demand sub-trial, it was not possible for new subjects to switch to another regimen, subjects who did not comply with on-demand treatment regimen were to be withdrawn. Subjects coming from main trial were allowed to switch back before completion of 6 months on-demand treatment. All subjects were offered participation until either turoctocog alfa was commercially available in relevant country or until trial, part of trial or a trial site was terminated by Novo Nordisk or a relevant authority for any reason in relevant country. Maximum treatment duration (27 Oct 2009 - 30 Jun 2016). On-Demand regimen: Dose level aimed at a post injection level of at least 0.50 IU/mL of turoctocog alfa for treatment of bleeds as they occurred and occasionally as preventive treatment.
Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. Excellent	124 Number of bleeds	189 Number of bleeds	72 Number of bleeds	565 Number of bleeds	1 Number of bleeds	150 Number of bleeds	94 Number of bleeds
Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. Good	62 Number of bleeds	103 Number of bleeds	103 Number of bleeds	382 Number of bleeds	6 Number of bleeds	22 Number of bleeds	105 Number of bleeds
Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. Moderate	17 Number of bleeds	37 Number of bleeds	19 Number of bleeds	91 Number of bleeds	0 Number of bleeds	2 Number of bleeds	11 Number of bleeds
Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. None	1 Number of bleeds	1 Number of bleeds	0 Number of bleeds	7 Number of bleeds	0 Number of bleeds	0 Number of bleeds	0 Number of bleeds
Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. Not known	0 Number of bleeds	0 Number of bleeds	0 Number of bleeds	1 Number of bleeds	0 Number of bleeds	0 Number of bleeds	0 Number of bleeds
Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. Missing	0 Number of bleeds	1 Number of bleeds	2 Number of bleeds	5 Number of bleeds	0 Number of bleeds	0 Number of bleeds	0 Number of bleeds

Adverse Events

Small Children (0 - <6 Years)

Serious events: 5 serious events

Other events: 23 other events

Deaths: 0 deaths

Older Children (6 - <12 Years)

Serious events: 9 serious events

Other events: 25 other events

Deaths: 0 deaths

Adolescents (12 - <18 Years)

Serious events: 6 serious events

Other events: 20 other events

Deaths: 0 deaths

Adults (≥18 Years)

Serious events: 21 serious events

Other events: 94 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Global Clinical Registry (GCR, 1452)

Novo Nordisk A/S

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER