Congenital Bleeding Disorder, Haemophilia A
Conditions
Brief summary
This trial is conducted globally. The aim of this trial is to evaluate the haemostatic effect of NNC 0129-0000-1003 during surgical procedures in subjects with haemophilia A.
Interventions
Bleeding preventive treatment administered i.v. before, during and after surgery. Individually adjusted doses.
Sponsors
Novo Nordisk A/S
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Informed consent obtained before any trial-related activities. (Trial-related activities are any procedure that would not have been performed during normal management of the subject.) * Ongoing participation in the pathfinder™2 (NN7088-3859) or the pathfinderTM 4 (NN7088-3861) trial and having received greater than or equal to 5 doses of N8-GP * Undergoing major surgery requiring daily monitoring of FVIII:C (FVIII activity) and wound status for at least 3 days * The patient and/or Legally Acceptable Representative (LAR) is capable of assessing a bleeding episode, keeping an eDiary, capable of home treatment of bleeding episodes and otherwise capable of following the trial procedures
Exclusion criteria
* Known or suspected hypersensitivity to trial product including allergy to hamster protein or related products * Previous withdrawal from the pathfinder™2 (NN7088-3859) or the pathfinderTM 4 (NN7088-3861) trial after administration of trial product, except interruption due to inclusion in this pathfinderTM 3 trial (NN7088-3860) * The receipt of any investigational medicinal product (except N8-GP) within 30 days prior to enrolment into the trial. (For Brazil, only: Participation in a previous clinical trial within one year prior to screening for this trial (Visit 1), unless there is a direct benefit to the research subject, at the Investigator's discretion) * FVIII inhibitors at least 0.6 BU (Bethesda Units)/mL at screening * Previous arterial thrombotic events (e.g. myocardial infarction and intracranial thrombosis) or previous deep venous thrombosis or pulmonary embolism (as defined by available medical records) * Immune modulating or chemotherapeutic medication * Any disease (liver, kidney, inflammatory and mental disorders included) or condition which, according to the Investigator's judgement, could imply a potential hazard to the patient, interfere with trial participation or trial outcome * Unwillingness, language or other barriers precluding adequate understanding and/or cooperation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Haemostatic Effect During Surgery Evaluated by the Four-point Scale, Assessed by the Investigator/Surgeon at the Day of Surgery - Four-point Response Scale: Excellent, Good, Moderate or None | Assessed by the Investigator/surgeon at the day of surgery | Haemostatic effect during surgery was evaluated on a four-point response scale as 'none', 'moderate', 'good' and 'excellent'. This was assessed after completion of surgery (defined as last stitch). Excellent: Better than expected/predicted in this type of procedure. Good: As expected in this type of procedure. Moderate: Less than optimal for the type of procedure but haemostatic response maintained without change of treatment regimen. None: Bleeding due to inadequate therapeutic response with adequate dosing, change of regimen required. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Haemostatic Effect of N8-GP During the Post-operative Period Days 1-6 | During the post-operative period, days 1-6 | Haemostatic effect during post-operative period days 1-6 as evaluated on a four-point response scale as 'none', 'moderate', 'good' and 'excellent'. Excellent: Better than expected/predicted in this type of procedure. Good: As expected in this type of procedure. Moderate: Less than optimal for the type of procedure but haemostatic response maintained without change of treatment regimen. None: Bleeding due to inadequate therapeutic response with adequate dosing, change of regimen required. |
| Haemostatic Effect of N8-GP During the Post-operative Period Days 7-14 | During the post-operative period, days 7-14 | Haemostatic effect during post-operative period days 1-6 and days 7-14 was evaluated on a four-point response scale as 'none', 'moderate', 'good' and 'excellent'. Excellent: Better than expected/predicted in this type of procedure. Good: As expected in this type of procedure. Moderate: Less than optimal for the type of procedure but haemostatic response maintained without change of treatment regimen. None: Bleeding due to inadequate therapeutic response with adequate dosing, change of regimen required. |
| Average Consumption of N8-GP During the Post-operative Period Days 1-6 | During the post-operative period, days 1-6 | Average consumption of N8-GP during post operative period days 1-6 is presented. Analysis population: Full analysis set included all subjects exposed to the trial drug (N8-GP) and completed surgery. |
| Incidence Rate of Inhibitors Against Factor VIII (FVIII) (≥0.6 BU/mL) | during the trial (2-5 weeks) | Incidence rate of inhibitors is the number of newly developed inhibitors per surgery. Development of FVIII inhibitors was measured by a validated Nijmegen modified Bethesda assay. A positive inhibitor test was defined as ≥0.6 bethesda unit. Number of participants with inhibitors at the end of trial is presented. |
| Estimated Blood Loss During Surgery | During surgery | The mean estimated blood loss following surgery is presented. Estimated blood loss (mL) was evaluated post surgery. |
| Average Consumption of N8-GP During Surgery | During surgery, defined as the time from knife to skin until last stitch | Average consumption of N8-GP, during surgery is presented. The time during surgery is defined from 'knife to skin' until 'last stitch'. |
| Length of Stay in the Hospital | During the trial (2-5 weeks) | Mean number of days stayed at the hospital during the trial. |
| Number of Days in Intensive Care | During the trial (2-5 weeks) | Mean number of days in the intensive care due to surgery during the trial is presented. |
| Adverse Events Reported During the Trial Period | During the trial (2-5 weeks) | Number of adverse event during the trial is presented. This includes events from the first trial related activity after the patient has signed the informed consent and until the end of trial (earliest at day 14). |
| Serious Adverse Events Reported During the Trial Period | During the trial (2-5 weeks) | Number of serious adverse event during the trial is presented. This includes events from the first trial related activity after the patient has signed the informed consent and until the end of trial (earliest at day 14). |
| Number of Transfusions During the Post-operative Period Days 1-6 | Post-operative period, days 1-6 | Number of blood product transfusions (transfusion of red blood cells) during the post-surgery period, Days 1-6 is presented. |
Countries
Australia, Brazil, Bulgaria, Croatia, Denmark, France, Germany, Hungary, Israel, Italy, Japan, Malaysia, Netherlands, Norway, Spain, Sweden, Switzerland, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
The trial was conducted at 26 sites in 13 countries, as follows: Australia (1 site), Denmark (1 site), France (3 sites), Hungary (1 site), Israel (1 site), Italy (2 sites), Japan (2 sites), Malaysia (1 site), Netherlands (1 site), Switzerland (2 sites), Turkey (3 sites), United Kingdom (4 sites) and United States (4 sites).
Pre-assignment details
36 participants were screened and exposed to the trial product. A total of 53 surgeries were planned in these 36 participants and 49 surgeries were completed. The results are analysed and presented based on the number of surgeries instead of number of participants. Participants in this trial were also enrolled in the NN7088-3859 trial.
Participants by arm
| Arm | Count |
|---|---|
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) Subjects (from trial NN7088-3859) undergoing major surgery received bleeding preventive treatment with turoctocog alfa pegol (N8-GP) before, during and after surgery. The trial product was administered as a slow bolus intravenous injection. Dosing was done at the investigators' discretion (except a fixed dose of 50 IU/kg at screening visit). The dose level of N8-GP during this trial was chosen following the coagulation factor 8 (FVIII) activity levels recommended by World Federation of Hemophilia (WFH) guidelines. The WFH guidelines for desired FVIII levels in major surgery are as follows: pre-surgery (day 0): 80-100%; post-surgery days 1-3: 60-80%; days 4-6: 40-60%; days 7-14: 30-50%. All subjects were treated with doses between 20-75 IU/kg for treatment of a bleeding episode. The maximum dose to be administered to a subject within 24 hours was 200 IU/kg. The total duration of the trial was 2-5 weeks. Upon completion of this trial, subjects returned to trial NN7088-3859. | 36 |
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) Subjects (from trial NN7088-3859) undergoing major surgery received bleeding preventive treatment with turoctocog alfa pegol (N8-GP) before, during and after surgery. The trial product was administered as a slow bolus intravenous injection. Dosing was done at the investigators' discretion (except a fixed dose of 50 IU/kg at screening visit). The dose level of N8-GP during this trial was chosen following the coagulation factor 8 (FVIII) activity levels recommended by World Federation of Hemophilia (WFH) guidelines. The WFH guidelines for desired FVIII levels in major surgery are as follows: pre-surgery (day 0): 80-100%; post-surgery days 1-3: 60-80%; days 4-6: 40-60%; days 7-14: 30-50%. All subjects were treated with doses between 20-75 IU/kg for treatment of a bleeding episode. The maximum dose to be administered to a subject within 24 hours was 200 IU/kg. The total duration of the trial was 2-5 weeks. Upon completion of this trial, subjects returned to trial NN7088-3859. | 53 |
| Total | 89 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal criterion | 1 |
Baseline characteristics
| Characteristic | NNC 0129-0000-1003 (Turoctocog Alfa Pegol) |
|---|---|
| Age, Continuous | 40.6 years STANDARD_DEVIATION 13.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 36 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 30 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 53 |
| other Total, other adverse events | 30 / 53 |
| serious Total, serious adverse events | 4 / 53 |
Outcome results
Primary
Haemostatic Effect During Surgery Evaluated by the Four-point Scale, Assessed by the Investigator/Surgeon at the Day of Surgery - Four-point Response Scale: Excellent, Good, Moderate or None
Haemostatic effect during surgery was evaluated on a four-point response scale as 'none', 'moderate', 'good' and 'excellent'. This was assessed after completion of surgery (defined as last stitch). Excellent: Better than expected/predicted in this type of procedure. Good: As expected in this type of procedure. Moderate: Less than optimal for the type of procedure but haemostatic response maintained without change of treatment regimen. None: Bleeding due to inadequate therapeutic response with adequate dosing, change of regimen required.
Time frame: Assessed by the Investigator/surgeon at the day of surgery
Population: Full analysis set included all subjects exposed to the trial drug (N8-GP). 'Number Analyzed' = number of surgeries evaluated. 49 surgeries were evaluated in 35 participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) | Haemostatic Effect During Surgery Evaluated by the Four-point Scale, Assessed by the Investigator/Surgeon at the Day of Surgery - Four-point Response Scale: Excellent, Good, Moderate or None | Excellent | 25 Surgeries |
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) | Haemostatic Effect During Surgery Evaluated by the Four-point Scale, Assessed by the Investigator/Surgeon at the Day of Surgery - Four-point Response Scale: Excellent, Good, Moderate or None | Good | 22 Surgeries |
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) | Haemostatic Effect During Surgery Evaluated by the Four-point Scale, Assessed by the Investigator/Surgeon at the Day of Surgery - Four-point Response Scale: Excellent, Good, Moderate or None | Moderate | 2 Surgeries |
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) | Haemostatic Effect During Surgery Evaluated by the Four-point Scale, Assessed by the Investigator/Surgeon at the Day of Surgery - Four-point Response Scale: Excellent, Good, Moderate or None | None | 0 Surgeries |
Secondary
Adverse Events Reported During the Trial Period
Number of adverse event during the trial is presented. This includes events from the first trial related activity after the patient has signed the informed consent and until the end of trial (earliest at day 14).
Time frame: During the trial (2-5 weeks)
Population: Safety analysis set (SAS) included all patients exposed to trial drug (N8-GP). 'Number Analyzed' = number of surgeries evaluated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) | Adverse Events Reported During the Trial Period | 127 adverse events |
Secondary
Average Consumption of N8-GP During Surgery
Average consumption of N8-GP, during surgery is presented. The time during surgery is defined from 'knife to skin' until 'last stitch'.
Time frame: During surgery, defined as the time from knife to skin until last stitch
Population: Full analysis set included all subjects exposed to the trial drug (N8-GP). 'Number Analyzed' = number of surgeries evaluated. N8-GP was administered during 1 surgery for 1 participant.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) | Average Consumption of N8-GP During Surgery | 20.7 IU/kg | 0 |
Secondary
Average Consumption of N8-GP During the Post-operative Period Days 1-6
Average consumption of N8-GP during post operative period days 1-6 is presented. Analysis population: Full analysis set included all subjects exposed to the trial drug (N8-GP) and completed surgery.
Time frame: During the post-operative period, days 1-6
Population: Full analysis set included all subjects exposed to the trial drug (N8-GP). 'Number Analyzed' = number of surgeries evaluated. 49 surgeries were evaluated in 35 participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) | Average Consumption of N8-GP During the Post-operative Period Days 1-6 | 33.0 IU/kg | Standard Deviation 10.2 |
Secondary
Estimated Blood Loss During Surgery
The mean estimated blood loss following surgery is presented. Estimated blood loss (mL) was evaluated post surgery.
Time frame: During surgery
Population: Full analysis set included all subjects exposed to the trial drug (N8-GP). 'Number Analyzed' = number of surgeries evaluated. 49 surgeries were evaluated in 35 participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) | Estimated Blood Loss During Surgery | 322.6 mL | Standard Deviation 745 |
Secondary
Haemostatic Effect of N8-GP During the Post-operative Period Days 1-6
Haemostatic effect during post-operative period days 1-6 as evaluated on a four-point response scale as 'none', 'moderate', 'good' and 'excellent'. Excellent: Better than expected/predicted in this type of procedure. Good: As expected in this type of procedure. Moderate: Less than optimal for the type of procedure but haemostatic response maintained without change of treatment regimen. None: Bleeding due to inadequate therapeutic response with adequate dosing, change of regimen required.
Time frame: During the post-operative period, days 1-6
Population: Full analysis set included all subjects exposed to the trial drug (N8-GP). 'Number Analyzed' = number of surgeries evaluated. 2 surgeries with 2 bleeding episodes were evaluated in 35 participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) | Haemostatic Effect of N8-GP During the Post-operative Period Days 1-6 | Excellent | 0 bleeding episodes |
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) | Haemostatic Effect of N8-GP During the Post-operative Period Days 1-6 | Good | 1 bleeding episodes |
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) | Haemostatic Effect of N8-GP During the Post-operative Period Days 1-6 | Moderate | 0 bleeding episodes |
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) | Haemostatic Effect of N8-GP During the Post-operative Period Days 1-6 | None | 0 bleeding episodes |
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) | Haemostatic Effect of N8-GP During the Post-operative Period Days 1-6 | Missing | 1 bleeding episodes |
Secondary
Haemostatic Effect of N8-GP During the Post-operative Period Days 7-14
Haemostatic effect during post-operative period days 1-6 and days 7-14 was evaluated on a four-point response scale as 'none', 'moderate', 'good' and 'excellent'. Excellent: Better than expected/predicted in this type of procedure. Good: As expected in this type of procedure. Moderate: Less than optimal for the type of procedure but haemostatic response maintained without change of treatment regimen. None: Bleeding due to inadequate therapeutic response with adequate dosing, change of regimen required.
Time frame: During the post-operative period, days 7-14
Population: Full analysis set included all subjects exposed to the trial drug (N8-GP). 'Number Analyzed' = number of surgeries evaluated. 2 surgeries with 2 bleeding episodes were evaluated in 35 participants.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) | Haemostatic Effect of N8-GP During the Post-operative Period Days 7-14 | Excellent | 1 bleeding episodes |
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) | Haemostatic Effect of N8-GP During the Post-operative Period Days 7-14 | Good | 1 bleeding episodes |
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) | Haemostatic Effect of N8-GP During the Post-operative Period Days 7-14 | Moderate | 0 bleeding episodes |
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) | Haemostatic Effect of N8-GP During the Post-operative Period Days 7-14 | None | 0 bleeding episodes |
Secondary
Incidence Rate of Inhibitors Against Factor VIII (FVIII) (≥0.6 BU/mL)
Incidence rate of inhibitors is the number of newly developed inhibitors per surgery. Development of FVIII inhibitors was measured by a validated Nijmegen modified Bethesda assay. A positive inhibitor test was defined as ≥0.6 bethesda unit. Number of participants with inhibitors at the end of trial is presented.
Time frame: during the trial (2-5 weeks)
Population: Safety analysis set (SAS) included all patients exposed to trial drug (N8-GP).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) | Incidence Rate of Inhibitors Against Factor VIII (FVIII) (≥0.6 BU/mL) | 0 Participants |
Secondary
Length of Stay in the Hospital
Mean number of days stayed at the hospital during the trial.
Time frame: During the trial (2-5 weeks)
Population: Full analysis set included all subjects exposed to the trial drug (N8-GP). 'Number Analyzed' = number of surgeries evaluated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) | Length of Stay in the Hospital | 10.00 days | Standard Deviation 8.9 |
Secondary
Number of Days in Intensive Care
Mean number of days in the intensive care due to surgery during the trial is presented.
Time frame: During the trial (2-5 weeks)
Population: Full analysis set included all subjects exposed to the trial drug (N8-GP). 'Number Analyzed' = number of surgeries evaluated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) | Number of Days in Intensive Care | 0.02 days | Standard Deviation 0.14 |
Secondary
Number of Transfusions During the Post-operative Period Days 1-6
Number of blood product transfusions (transfusion of red blood cells) during the post-surgery period, Days 1-6 is presented.
Time frame: Post-operative period, days 1-6
Population: Full analysis set included all subjects exposed to the trial drug (N8-GP). 'Number Analyzed' = number of surgeries evaluated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) | Number of Transfusions During the Post-operative Period Days 1-6 | 9 blood transfusions |
Secondary
Serious Adverse Events Reported During the Trial Period
Number of serious adverse event during the trial is presented. This includes events from the first trial related activity after the patient has signed the informed consent and until the end of trial (earliest at day 14).
Time frame: During the trial (2-5 weeks)
Population: Safety analysis set (SAS) included all patients exposed to trial drug (N8-GP). 'Number Analyzed' = number of surgeries evaluated.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| NNC 0129-0000-1003 (Turoctocog Alfa Pegol) | Serious Adverse Events Reported During the Trial Period | 5 serious adverse event |