Congenital Bleeding Disorder, Haemophilia A
Conditions
Brief summary
This trial is conducted in Asia, Europe, Japan, Oceania, North America and South America. The aim of the trial is to investigate the safety and efficacy of turoctocog alfa (N8) in Haemophilia A patients. The trial is an extension to trials NN7008-3543 (start: March 2009, stop: September 2011) and NN7008-3545 (start: May 2010, stop: November 2011) and the pharmacokinetic trials NN7008-3600 (start: November 2010, stop: October 2011), NN7008-3893 (start: June 2011, stop: September 2011) and NN7008-4015 (start: August 2012, stop: March 2013).
Interventions
DRUGturoctocog alfa
The preventative treatment is administered intravenously (i.v.) at specific intervals either every second day or three times a week. Bleeding treatment will be administered if a bleed should occur.
Sponsors
Novo Nordisk A/S
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
6 Months to 70 Years
Healthy volunteers
No
Inclusion criteria
* Informed Consent obtained before any trial-related activities * Completion of trial NN7008-3543 or paediatric trial NN7008-3545 or Japanese trial NN7008-3600 or pharmacokinetic trial NN7008-3893 or NN7008-4015
Exclusion criteria
* Previous participation in the current trial (defined as withdrawal) or withdrawn subjects from NN7008-3522, NN7008-3543, NN7008-3545, NN7008-3600, NN7008-3893 or NN7008-4015 after administration of trial product
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Development of FVIII Inhibitors (Greater Than or Equal to 0.6 Bethesda Units (BU)/mL) | After 90 months | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Adverse Events and Serious Adverse Events | After 90 months | The number of adverse events and serious adverse events reported during the main trial and the on-demand sub-trial (during 90 months). |
| Annualised Bleeding Rate Reported During the Prevention Period (Only Applicable for Subjects in the Preventive Regimen) | After 90 months | The number of bleeding episodes per year reported during the prevention period (during 90 months). |
| Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | After 90 months | 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). |
Countries
Brazil, Croatia, Germany, Israel, Italy, Japan, Latvia, Lithuania, Malaysia, North Macedonia, Poland, Puerto Rico, Russia, Serbia, Spain, Switzerland, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
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).
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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) | 27 |
| 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). | 28 |
| 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). | 23 |
| 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). | 135 |
| Total | 213 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 2 |
| Overall Study | Choose to join Pathfinder trial™ + other | 7 | 7 | 3 | 46 |
| Overall Study | Protocol Violation | 0 | 0 | 1 | 2 |
| Overall Study | Withdrawal criteria | 0 | 1 | 3 | 9 |
Baseline characteristics
| Characteristic | Small Children (0 - <6 Years) | Older Children (6 - <12 Years) | Adolescents (12 - <18 Years) | Adults (≥18 Years) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 4.6 years STANDARD_DEVIATION 1.4 | 9.0 years STANDARD_DEVIATION 1.8 | 14.9 years STANDARD_DEVIATION 1.7 | 32.0 years STANDARD_DEVIATION 11.5 | 23.6 years STANDARD_DEVIATION 14.6 |
| Age, Customized Adolescents (12 - <18 Years) | 0 participants | 0 participants | 23 participants | 0 participants | 23 participants |
| Age, Customized Adults (≥18 Years) | 0 participants | 0 participants | 0 participants | 135 participants | 135 participants |
| Age, Customized Older children (6 - <12 Years) | 0 participants | 28 participants | 0 participants | 0 participants | 28 participants |
| Age, Customized Small children (0 - <6 years) | 27 participants | 0 participants | 0 participants | 0 participants | 27 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 27 Participants | 28 Participants | 23 Participants | 135 Participants | 213 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 23 / 27 | 25 / 28 | 20 / 23 | 94 / 135 |
| serious Total, serious adverse events | 5 / 27 | 9 / 28 | 6 / 23 | 21 / 135 |
Outcome results
Primary
Frequency of Development of FVIII Inhibitors (Greater Than or Equal to 0.6 Bethesda Units (BU)/mL)
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.
Time frame: After 90 months
Population: Full analysis set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Small Children (0 - <6 Years) | Frequency of Development of FVIII Inhibitors (Greater Than or Equal to 0.6 Bethesda Units (BU)/mL) | 0 subjects |
| Older Children (6 - <12 Years) | Frequency of Development of FVIII Inhibitors (Greater Than or Equal to 0.6 Bethesda Units (BU)/mL) | 0 subjects |
| Adolescents (12 - <18 Years) | Frequency of Development of FVIII Inhibitors (Greater Than or Equal to 0.6 Bethesda Units (BU)/mL) | 0 subjects |
| Adults (≥18 Years) | Frequency of Development of FVIII Inhibitors (Greater Than or Equal to 0.6 Bethesda Units (BU)/mL) | 0 subjects |
Comparison: A one-sided 95% upper confidence limit was based on an exact calculation for a binomial distribution.
Secondary
Annualised Bleeding Rate Reported During the Prevention Period (Only Applicable for Subjects in the Preventive Regimen)
The number of bleeding episodes per year reported during the prevention period (during 90 months).
Time frame: After 90 months
Population: Full Analysis Set. Number of subjects analysed=Subjects who received preventive regimen and were evaluable for the outcome.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Small Children (0 - <6 Years) | Annualised Bleeding Rate Reported During the Prevention Period (Only Applicable for Subjects in the Preventive Regimen) | 1.08 Bleeding episodes/year |
| Older Children (6 - <12 Years) | Annualised Bleeding Rate Reported During the Prevention Period (Only Applicable for Subjects in the Preventive Regimen) | 1.57 Bleeding episodes/year |
| Adolescents (12 - <18 Years) | Annualised Bleeding Rate Reported During the Prevention Period (Only Applicable for Subjects in the Preventive Regimen) | 1.57 Bleeding episodes/year |
| Adults (≥18 Years) | Annualised Bleeding Rate Reported During the Prevention Period (Only Applicable for Subjects in the Preventive Regimen) | 1.37 Bleeding episodes/year |
Secondary
Frequency of Adverse Events and Serious Adverse Events
The number of adverse events and serious adverse events reported during the main trial and the on-demand sub-trial (during 90 months).
Time frame: After 90 months
Population: Safety Analysis Set includes all dosed subjects with data after dosing.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Small Children (0 - <6 Years) | Frequency of Adverse Events and Serious Adverse Events | Adverse events | 180 Number of Events |
| Small Children (0 - <6 Years) | Frequency of Adverse Events and Serious Adverse Events | Serious adverse events | 6 Number of Events |
| Older Children (6 - <12 Years) | Frequency of Adverse Events and Serious Adverse Events | Serious adverse events | 8 Number of Events |
| Older Children (6 - <12 Years) | Frequency of Adverse Events and Serious Adverse Events | Adverse events | 204 Number of Events |
| Adolescents (12 - <18 Years) | Frequency of Adverse Events and Serious Adverse Events | Adverse events | 240 Number of Events |
| Adolescents (12 - <18 Years) | Frequency of Adverse Events and Serious Adverse Events | Serious adverse events | 6 Number of Events |
| Adults (≥18 Years) | Frequency of Adverse Events and Serious Adverse Events | Adverse events | 636 Number of Events |
| Adults (≥18 Years) | Frequency of Adverse Events and Serious Adverse Events | Serious adverse events | 27 Number of Events |
Secondary
Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds.
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).
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Small Children (0 - <6 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | None | 1 Number of bleeds |
| Small Children (0 - <6 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Moderate | 17 Number of bleeds |
| Small Children (0 - <6 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Missing | 0 Number of bleeds |
| Small Children (0 - <6 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Not known | 0 Number of bleeds |
| Small Children (0 - <6 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Good | 62 Number of bleeds |
| Small Children (0 - <6 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Excellent | 124 Number of bleeds |
| Older Children (6 - <12 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Good | 103 Number of bleeds |
| Older Children (6 - <12 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | None | 1 Number of bleeds |
| Older Children (6 - <12 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Missing | 1 Number of bleeds |
| Older Children (6 - <12 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Excellent | 189 Number of bleeds |
| Older Children (6 - <12 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Moderate | 37 Number of bleeds |
| Older Children (6 - <12 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Not known | 0 Number of bleeds |
| Adolescents (12 - <18 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Good | 103 Number of bleeds |
| Adolescents (12 - <18 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Excellent | 72 Number of bleeds |
| Adolescents (12 - <18 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Moderate | 19 Number of bleeds |
| Adolescents (12 - <18 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | None | 0 Number of bleeds |
| Adolescents (12 - <18 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Not known | 0 Number of bleeds |
| Adolescents (12 - <18 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Missing | 2 Number of bleeds |
| Adults (≥18 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Missing | 5 Number of bleeds |
| Adults (≥18 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | None | 7 Number of bleeds |
| Adults (≥18 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Excellent | 565 Number of bleeds |
| Adults (≥18 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Not known | 1 Number of bleeds |
| Adults (≥18 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Good | 382 Number of bleeds |
| Adults (≥18 Years) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Moderate | 91 Number of bleeds |
| Adolescents (12-<18 Years)-(On-Demand Regimen [Main Trial]) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Excellent | 1 Number of bleeds |
| Adolescents (12-<18 Years)-(On-Demand Regimen [Main Trial]) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Moderate | 0 Number of bleeds |
| Adolescents (12-<18 Years)-(On-Demand Regimen [Main Trial]) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | None | 0 Number of bleeds |
| Adolescents (12-<18 Years)-(On-Demand Regimen [Main Trial]) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Not known | 0 Number of bleeds |
| Adolescents (12-<18 Years)-(On-Demand Regimen [Main Trial]) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Missing | 0 Number of bleeds |
| Adolescents (12-<18 Years)-(On-Demand Regimen [Main Trial]) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Good | 6 Number of bleeds |
| Adults (>=18 Years)-(On-Demand Regimen [Main Trial]) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Excellent | 150 Number of bleeds |
| Adults (>=18 Years)-(On-Demand Regimen [Main Trial]) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Missing | 0 Number of bleeds |
| Adults (>=18 Years)-(On-Demand Regimen [Main Trial]) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Good | 22 Number of bleeds |
| Adults (>=18 Years)-(On-Demand Regimen [Main Trial]) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Not known | 0 Number of bleeds |
| Adults (>=18 Years)-(On-Demand Regimen [Main Trial]) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Moderate | 2 Number of bleeds |
| Adults (>=18 Years)-(On-Demand Regimen [Main Trial]) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | None | 0 Number of bleeds |
| Adults (>=18 Years)-(On-Demand Regimen [Sub-trial]) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | None | 0 Number of bleeds |
| Adults (>=18 Years)-(On-Demand Regimen [Sub-trial]) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Missing | 0 Number of bleeds |
| Adults (>=18 Years)-(On-Demand Regimen [Sub-trial]) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Moderate | 11 Number of bleeds |
| Adults (>=18 Years)-(On-Demand Regimen [Sub-trial]) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Good | 105 Number of bleeds |
| Adults (>=18 Years)-(On-Demand Regimen [Sub-trial]) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Excellent | 94 Number of bleeds |
| Adults (>=18 Years)-(On-Demand Regimen [Sub-trial]) | Haemostatic Response to Turoctocog Alfa (None, Moderate, Good or Excellent) in Treatment of Bleeds. | Not known | 0 Number of bleeds |