Hemophilia A
Conditions
Brief summary
Prospective, multinational, non-interventional post-authorisation study to collect additional clinical data and to ensure consistency in the long-term between the outcome from pre-authorisation clinical studies (in 135 previously treated paediatric and adult patients) and routine clinical practice. Besides aspects such as general product safety and efficacy, there will be a focus on immunogenicity, particularly on inhibitor development. The diagnosis of FVIII inhibitor will be based on clinical observations and confirmed by FVIII inhibitor testing in the laboratory.
Interventions
None listed
Sponsors
Octapharma
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
MALE
Healthy volunteers
No
Inclusion criteria
* Haemophilia A (FVIII:C ≤ 2%) based on medical history; at least 100 patients should have severe haemophilia A (FVIII:C \< 1%) * Male patients of any age * Previous treatment with a FVIII concentrate for more than 150 EDs * Availability of detailed documentation (patient diary, log book, etc.) covering either the last 50 EDs or the last 2 years per patient to confirm treatment modality (i.e., prophylaxis, on-demand, recent surgery, or immune tolerance induction) * Inhibitor negative (\< 0.6 BU) at study entry as confirmed by a recovery test with previous FVIII product and inhibitor test in a central laboratory * Immunocompetence (CD4+ count \> 200/µL), HIV-negative, or having a viral load \< 200 particles/µL or \< 400,000 copies/mL * Decision to prescribe Human-cl rhFVIII before enrolment into the study * Written informed consent by the patient or the patient's parent or legal guardian
Exclusion criteria
* Patients treated with any investigational medicinal product (IMP) except FVIII IMP within 30 days prior to the Screening Visit or patients planning to undergo treatment with any IMP other than Human-cl rhFVIII are not eligible for enrolment into the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With FVIII Inhibitors | Screening through to study completion (minimum 1.7 months; maximum 31.6 months) | FVIII inhibitors will be determined based on clinical observations and confirmed by FVIII inhibitor testing in the laboratory. |
| Number of Patients With Adverse Drug Reactions | Recorded from screening through to study completion (minimum 1.7 months; maximum 31.6 months) | Adverse drug reactions (ADRs) including hypersensitivity reactions will be recorded by patients in treatment diaries which will be reviewed at each Follow-up Visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Rate of Breakthrough Bleeds to Assess Efficacy in Prophylactic Treatment | Monitored throughout the study from screening through to study completion (minimum 3.7 months; maximum 21.2 months) | Total number of bleeding episodes under prophylaxis treatment divided by the duration of prophylactic phase (in years) |
| Assessment of the Efficacy of On-demand Treatment of Bleeding Episodes (BEs) Based on a 4-point Efficacy Scale | Monitored throughout the study from screening through to study completion (minimum 1.7 months; maximum 31.6 months) | At the end of a BE, treatment efficacy was to be assessed either by the patient (or the patient's parent or legal guardian) or by the treating physician in case of on-site treatment using a 4-point scale including the four items 'excellent,' 'good,' moderate,' and 'none.' Excellent result was defined as abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single injection. Good was definite pain relief and/or improvement in signs of bleeding within approximately 8-12 hours after an injection requiring up to 2 injections for complete resolution. Moderate was probable or slight beneficial effect within approximately 12 hours after the first injection requiring more than two injections for complete resolution. None was no improvement after 12 hours, or worsening of symptoms, requiring more than 2 injections for complete resolution. |
| Overall Assessment of the Effectiveness of Surgical Prophylaxis by the Treating Physicians | From start of surgery until end of post-operative period | At the end of the postoperative period, an overall assessment of the efficacy of treatment in the pre-, peri-, and postoperative periods using the 'excellent,' 'good,' moderate,' and 'none' scale will be done jointly by the surgeon and the hematologist. Based on this assessment, efficacy ratings assessed as either 'excellent' or 'good' will be considered 'successfully treated'. |
| Assessment of the Efficacy of Treatment of Bleeding Episodes (BEs) Based on a 4-point Efficacy Scale | Recorded from screening through to study completion (minimum 1.7 months; maximum 31.6 months) | At the end of a BE, treatment efficacy was to be assessed either by the patient (or the patient's parent or legal guardian) or by the treating physician in case of on-site treatment using a 4-point scale including the four items 'excellent', 'good', 'moderate', and 'none.' Excellent result was defined as abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single injection. Good was definite pain relief and/or improvement in signs of bleeding within approximately 8-12 hours after an injection requiring up to 2 injections for complete resolution. Moderate was probable or slight beneficial effect within approximately 12 hours after the first injection requiring more than two injections for complete resolution. None was no improvement after 12 hours, or worsening of symptoms, requiring more than 2 injections for complete resolution. |
Countries
Argentina, Belarus, Czechia, Ecuador, France, Guatemala, Italy, Lithuania, Norway, Portugal, Slovakia, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nuwiq® (Human-cl rhFVIII) SAF Population The safety (SAF) population consist of all patients who received at least one infusion of Human-cl rhFVIII (n=78) | 78 |
| Total | 78 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Limited access to study medication | 3 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Protocol Violation | 9 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Nuwiq® (Human-cl rhFVIII) SAF Population |
|---|---|
| Age, Customized Age 12-<18 yrs | 12 Participants |
| Age, Customized Age <12 yrs | 40 Participants |
| Age, Customized Age >18 yrs | 26 Participants |
| BMI 12-<18 yrs | 23.6 kg/m^2 STANDARD_DEVIATION 5.46 |
| BMI <12 yrs | 17.0 kg/m^2 STANDARD_DEVIATION 3.34 |
| BMI >18 yrs | 25.5 kg/m^2 STANDARD_DEVIATION 4.65 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 25 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 53 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Factor VIII gene defect Intron 22-Inversion | 17 Participants |
| Factor VIII gene defect Large Deletion/Insertion | 1 Participants |
| Factor VIII gene defect Missense Mutation | 2 Participants |
| Factor VIII gene defect Nonsense Mutation | 4 Participants |
| Factor VIII gene defect Other | 9 Participants |
| Factor VIII gene defect Small Deletion/Insertion | 5 Participants |
| Factor VIII gene defect Stop-Mutation | 4 Participants |
| Factor VIII gene defect Unknown | 36 Participants |
| Factor VIII Inhibitor History No | 68 Participants |
| Factor VIII Inhibitor History Yes | 10 Participants |
| Family history of Haemophilia No | 31 Participants |
| Family history of Haemophilia Yes | 47 Participants |
| Height 12-<18 yrs | 168.8 centimeters STANDARD_DEVIATION 9.73 |
| Height <12 yrs | 112 centimeters STANDARD_DEVIATION 17.59 |
| Height >18 yrs | 172.9 centimeters STANDARD_DEVIATION 7.88 |
| Race/Ethnicity, Customized Patient race American Indian or Alaska Native | 7 Participants |
| Race/Ethnicity, Customized Patient race Asian | 0 Participants |
| Race/Ethnicity, Customized Patient race Black or African American | 1 Participants |
| Race/Ethnicity, Customized Patient race More than one race | 0 Participants |
| Race/Ethnicity, Customized Patient race Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race/Ethnicity, Customized Patient race Other | 9 Participants |
| Race/Ethnicity, Customized Patient race White | 61 Participants |
| Severity of Haemophilia A Moderate | 10 Participants |
| Severity of Haemophilia A Severe | 68 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 78 Participants |
| Weight 12-<18 yrs | 67.1 kilograms STANDARD_DEVIATION 15.55 |
| Weight <12 yrs | 21.7 kilograms STANDARD_DEVIATION 8.3 |
| Weight >18 yrs | 76.6 kilograms STANDARD_DEVIATION 17.21 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 78 |
| other Total, other adverse events | 0 / 78 |
| serious Total, serious adverse events | 0 / 78 |
Outcome results
Primary
Number of Patients With Adverse Drug Reactions
Adverse drug reactions (ADRs) including hypersensitivity reactions will be recorded by patients in treatment diaries which will be reviewed at each Follow-up Visit.
Time frame: Recorded from screening through to study completion (minimum 1.7 months; maximum 31.6 months)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® | Number of Patients With Adverse Drug Reactions | 0 Participants |
Primary
Number of Patients With FVIII Inhibitors
FVIII inhibitors will be determined based on clinical observations and confirmed by FVIII inhibitor testing in the laboratory.
Time frame: Screening through to study completion (minimum 1.7 months; maximum 31.6 months)
Population: FVIII inhibitor testing could be carried out at any time at the physician's discretion. Patients were checked for clinical symptoms suggesting FVIII inhibitor development, any suspicion of inhibitor formation was to be investigated by FVIII inhibitor testing. No symptoms led to suspicion of inhibitor formation in any patient treated with Nuwiq®. Within the FAS population, inhibitor levels were tested in 40 patients at screening, 44 between screening and completion and 21 at study completion.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® | Number of Patients With FVIII Inhibitors | 0 Participants |
| FVIII Inhibitors Detected Between Screening and Completion in Patients Treated With Nuwiq® | Number of Patients With FVIII Inhibitors | 0 Participants |
| FVIII Inhibitors Detected at Completion in Patients Treated With Nuwiq® (Human-cl rhFVIII) | Number of Patients With FVIII Inhibitors | 0 Participants |
Secondary
Annualized Rate of Breakthrough Bleeds to Assess Efficacy in Prophylactic Treatment
Total number of bleeding episodes under prophylaxis treatment divided by the duration of prophylactic phase (in years)
Time frame: Monitored throughout the study from screening through to study completion (minimum 3.7 months; maximum 21.2 months)
Population: Of the 77 participants within the prophylactic treatment group, 74 patients had at least 3 months under a prophylactic regimen and had at least one bleeding episode and were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® | Annualized Rate of Breakthrough Bleeds to Assess Efficacy in Prophylactic Treatment | All bleeding events | 2.39 Number of bleeding episodes per year |
| FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® | Annualized Rate of Breakthrough Bleeds to Assess Efficacy in Prophylactic Treatment | Spontaneous bleeding events | 0.00 Number of bleeding episodes per year |
| FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® | Annualized Rate of Breakthrough Bleeds to Assess Efficacy in Prophylactic Treatment | Traumatic bleeding events | 0.00 Number of bleeding episodes per year |
Secondary
Assessment of the Efficacy of On-demand Treatment of Bleeding Episodes (BEs) Based on a 4-point Efficacy Scale
At the end of a BE, treatment efficacy was to be assessed either by the patient (or the patient's parent or legal guardian) or by the treating physician in case of on-site treatment using a 4-point scale including the four items 'excellent,' 'good,' moderate,' and 'none.' Excellent result was defined as abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single injection. Good was definite pain relief and/or improvement in signs of bleeding within approximately 8-12 hours after an injection requiring up to 2 injections for complete resolution. Moderate was probable or slight beneficial effect within approximately 12 hours after the first injection requiring more than two injections for complete resolution. None was no improvement after 12 hours, or worsening of symptoms, requiring more than 2 injections for complete resolution.
Time frame: Monitored throughout the study from screening through to study completion (minimum 1.7 months; maximum 31.6 months)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® | Assessment of the Efficacy of On-demand Treatment of Bleeding Episodes (BEs) Based on a 4-point Efficacy Scale | None | 0 Number of Bleeding episodes |
| FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® | Assessment of the Efficacy of On-demand Treatment of Bleeding Episodes (BEs) Based on a 4-point Efficacy Scale | Excellent | 50 Number of Bleeding episodes |
| FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® | Assessment of the Efficacy of On-demand Treatment of Bleeding Episodes (BEs) Based on a 4-point Efficacy Scale | Good | 4 Number of Bleeding episodes |
| FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® | Assessment of the Efficacy of On-demand Treatment of Bleeding Episodes (BEs) Based on a 4-point Efficacy Scale | Moderate | 1 Number of Bleeding episodes |
Secondary
Assessment of the Efficacy of Treatment of Bleeding Episodes (BEs) Based on a 4-point Efficacy Scale
At the end of a BE, treatment efficacy was to be assessed either by the patient (or the patient's parent or legal guardian) or by the treating physician in case of on-site treatment using a 4-point scale including the four items 'excellent', 'good', 'moderate', and 'none.' Excellent result was defined as abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single injection. Good was definite pain relief and/or improvement in signs of bleeding within approximately 8-12 hours after an injection requiring up to 2 injections for complete resolution. Moderate was probable or slight beneficial effect within approximately 12 hours after the first injection requiring more than two injections for complete resolution. None was no improvement after 12 hours, or worsening of symptoms, requiring more than 2 injections for complete resolution.
Time frame: Recorded from screening through to study completion (minimum 1.7 months; maximum 31.6 months)
Population: Analysis was only performed on patients in the prophylactic treatment group who experienced bleeding episode that required treatment with Nuwiq. Of the 77 patients in the prophylactic treatment group, 48 patients experienced a BE that required treatment with Nuwiq and were assessed using the 4-point efficacy scale
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® | Assessment of the Efficacy of Treatment of Bleeding Episodes (BEs) Based on a 4-point Efficacy Scale | None | 3 Bleeding episodes |
| FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® | Assessment of the Efficacy of Treatment of Bleeding Episodes (BEs) Based on a 4-point Efficacy Scale | Excellent | 167 Bleeding episodes |
| FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® | Assessment of the Efficacy of Treatment of Bleeding Episodes (BEs) Based on a 4-point Efficacy Scale | Good | 50 Bleeding episodes |
| FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® | Assessment of the Efficacy of Treatment of Bleeding Episodes (BEs) Based on a 4-point Efficacy Scale | Moderate | 26 Bleeding episodes |
Secondary
Overall Assessment of the Effectiveness of Surgical Prophylaxis by the Treating Physicians
At the end of the postoperative period, an overall assessment of the efficacy of treatment in the pre-, peri-, and postoperative periods using the 'excellent,' 'good,' moderate,' and 'none' scale will be done jointly by the surgeon and the hematologist. Based on this assessment, efficacy ratings assessed as either 'excellent' or 'good' will be considered 'successfully treated'.
Time frame: From start of surgery until end of post-operative period
Population: A total of 4 patients had 6 surgeries that were treated with Nuwiq®. Two of these surgeries were minor and 4 were major. Five surgeries had an overall efficacy assessment performed jointly by the hematologist and surgeon. One of the six surgeries was treated pre-op with another FVIII product and post-op with Nuwiq® and therefore an assessment of Nuwiq® efficacy could not be performed
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® | Overall Assessment of the Effectiveness of Surgical Prophylaxis by the Treating Physicians | Moderate | 0 Surgeries |
| FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® | Overall Assessment of the Effectiveness of Surgical Prophylaxis by the Treating Physicians | Excellent | 5 Surgeries |
| FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® | Overall Assessment of the Effectiveness of Surgical Prophylaxis by the Treating Physicians | Good | 0 Surgeries |
| FVIII Inhibitors Detected at Screening in Patients Treated With Nuwiq® | Overall Assessment of the Effectiveness of Surgical Prophylaxis by the Treating Physicians | None | 0 Surgeries |