Severe Hemophilia A
Conditions
Brief summary
The purpose of this study is to obtain additional data on the safety and efficacy of Wilate in PTPs with hemophilia A with at least 150 previous exposure days (EDs) to a FVIII concentrate who undergo prophylactic treatment with Wilate for 6 months and at least 50 EDs, thus supplementing the existing database to obtain approval of Wilate for the indication hemophilia A in the USA.
Interventions
DRUGWilate
Sponsors
Octapharma
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
1. Severe hemophilia A (\<1% FVIII:C) according to medical history 2. Male patients aged ≥12 years 3. Previous treatment with a FVIII concentrate for at least 150 exposure days (EDs) 4. Immunocompetence (CD4+ count \>200/µL) 5. Good documentation of the historical bleeding rate (at least for the 6 months preceding study start) 6. Voluntarily given, fully informed written and signed consent obtained by the patient (or parent/legal guardian in case of adolescents) before any study-related procedures are conducted Whenever possible, the interval between the Screening Visit and the PK or Non-PK Visit should not exceed 30 days. If the 30-day interval is exceeded, determination of the CD4+ count is to be repeated and must be \>200/µL for patients to be enrolled (i.e., exclusion criterion no. 4).
Exclusion criteria
1. Any coagulation disorders other than hemophilia A 2. History of FVIII inhibitor activity (≥0.6 BU) or detectable FVIII inhibitory anti-bodies (≥0.6 BU using the Nijmegen modification of the Bethesda assay) at screening, as determined by the central laboratory 3. Severe liver or kidney diseases (alanine aminotransferase \[ALAT\] and aspartate transaminase \[ASAT\] levels \>5 times of upper limit of normal, creatinine\>120 µmol/L) 4. Patients receiving or scheduled to receive immunomodulating drugs (other than anti-retroviral chemotherapy) such as alpha-interferon, prednisone (equivalent to \>10 mg/day), or similar drugs 5. Treatment with any investigational medicinal product in another interventional clinical study currently or within 4 weeks before enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Annualized Bleeding Rate (TABR) | 6 months | The total number of bleeding events (BEs) was documented by patients in a patient diary (together with the investigator in case of on-site treatments), which was reviewed at each follow-up visit by site personnel. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Spontaneous Annualized Bleeding Rate (SABR) | 6 months | The number of spontaneous bleeding events (BEs) was documented by patients in a patient diary (together with the investigator in case of on-site treatments), which was reviewed at each follow-up visit by site personnel. |
| Efficacy of Wilate in the Treatment of Breakthrough BEs | 6 months | The proportion of BEs successfully treated with Wilate were documented by the patient (together with the investigator in case of on-site treatments) in the patient diary for all BEs according to a 4-point hemostatic efficacy scale including the four items: 'excellent,' 'good,' moderate,' and 'none', where 'excellent' was defined as Abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single injection (best outcome) and 'none' was defined as No improvement within 12 hours, or worsening of symptoms, requiring more than two injections for complete resolution (worst outcome). All efficacy ratings assessed as either 'excellent' or 'good' were considered 'successfully treated.' |
| Wilate Consumption Data (Average Total Normdose of FVIII IU/kg Per Month of Study) for Prophylaxis | 6 months | The average consumption of Wilate per month of study (IU/kg) for all patients receiving prophylaxis. |
| Pharmacokinetic (PK) Assessment (Area Under the Curve [AUC] Norm) of FVIII:C | Initial PK visit (Day -1) and PK study completion visit (6 months); data collected 1 h prior to injection and 15 min, 1 h, 3 h, 6 h, 9 h, 24 h, 30 h and 48 h after the end of injection | PK assessments of FVIII:C were conducted using the one-stage (OS) assay. The value of the AUCnorm of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study. |
| Pharmacokinetic (PK) Assessment (in Vivo Half-Life (t1/2)) of FVIII:C | Initial PK assessment (Day -1) and PK study completion visit (6 months); data collected 1 h prior to infusion and 15 min, 1 h, 3 h, 6 h, 9 h, 24 h, 30 h and 48 h after the end of injection | PK assessments of FVIII:C were conducted using the one-stage (OS) assay. The in vivo half-life of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study. |
| Pharmacokinetic (PK) Assessment (Maximum Plasma Concentration [Cmax]) of FVIII:C | Initial PK assessment (Day -1) and 6 months | PK assessments of FVIII:C were conducted using the one-stage (OS) assay. The maximum plasma concentration of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study. |
| Association Between ABO Blood Type and the FVIII:C Half-life of Wilate (OS Assay) | 6 months | Analysis of variance (ANOVA) was used in an exploratory sense to assess an association between ABO blood type and the FVIII:C half-life of Wilate. This was analyzed by calculating the mean square in a one-stage assay. |
| Association Between VWF:Ag Concentration and the FVIII:C Half-life of Wilate | 6 months | ANOVA was used in an exploratory sense to assess an association between VWF:Ag with the FVIII:C half-life of Wilate. This was analyzed by calculating the mean square in a one-stage assay. |
| Safety and Tolerability of Wilate by Monitoring Adverse Events (AEs) Throughout the Study | 6 months | At each (scheduled or unscheduled) study visit, AEs were documented by the investigator throughout the study. |
| Immunogenicity of Wilate by Testing for FVIII Inhibitors | 6 months | FVIII inhibitor activity was determined at each study visit before the injection of Wilate using the modified Bethesda assay (Nijmegen modification). |
| Virus Safety Measured by the Number of Parvovirus B19 Seroconversions Between Baseline (BL) and End of Study | 6 months | Virus safety was evaluated by taking a plasma sample for parvovirus B19 antibody testing before the first injection of Wilate. All patients negative at screening were tested again at the study completion visit. The number with Parvovirus B19 seroconversions between BL and end of study was recorded. |
| Incremental in Vivo Recovery (IVR) of Wilate Over Time | Baseline, 3 and 6 months | The rise in FVIII activity in IU/dl per unit dose administered in IU/kg was determined from all patients at baseline, 3 and 6 months, using the OS assay. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Wilate in Surgical Prophylaxis | 6 months | Hemostatic efficacy was assessed at the end of surgery by the surgeon and at end of the postoperative period by the hematologist, using a 4-point hemostatic efficacy scale including the four items: 'excellent' (best possible outcome), 'good', 'moderate' and 'none' (worst outcome). Overall efficacy was assessed by the investigator, taking both the intra and postoperative assessments into account, and using the 'excellent,' 'good,' moderate,' and 'none' scale. |
Countries
Bulgaria, Hungary, Poland, Romania, Russia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Wilate SAF population (All patients who received at least one administration of Wilate during the study (N=55) | 55 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Wilate |
|---|---|
| Age, Continuous | 35.0 years STANDARD_DEVIATION 12.3 |
| Blood groups 0 | 19 Participants |
| Blood groups A | 23 Participants |
| Blood groups AB | 5 Participants |
| Blood groups B | 8 Participants |
| Body mass index (BMI) | 26.8 kg/m2 STANDARD_DEVIATION 5.8 |
| Previous annualized bleeding rate (ABR) | 32.98 No. BEs per patient per year STANDARD_DEVIATION 39.12 |
| Previous Factor (F) VIII treatment Combination | 5 Participants |
| Previous Factor (F) VIII treatment On-demand | 32 Participants |
| Previous Factor (F) VIII treatment Prophylaxis | 18 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 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 | 55 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 55 Participants |
| von Willebrand factor activity (VWF:Ac) | 103.7 IU/dL STANDARD_DEVIATION 39.5 |
| von Willebrand factor antigen (VWF:Ag) | 118.4 IU/dL STANDARD_DEVIATION 78.9 |
| Weight | 83.3 kg STANDARD_DEVIATION 21.4 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 55 |
| other Total, other adverse events | 12 / 55 |
| serious Total, serious adverse events | 0 / 55 |
Outcome results
Primary
Total Annualized Bleeding Rate (TABR)
The total number of bleeding events (BEs) was documented by patients in a patient diary (together with the investigator in case of on-site treatments), which was reviewed at each follow-up visit by site personnel.
Time frame: 6 months
Population: The total annualized bleeding rate (TABR) was calculated for all patients included in the PP population (N=52).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Wilate | Total Annualized Bleeding Rate (TABR) | 2.10 No. of BEs / year (ABR) | Standard Deviation 3.44 |
Comparison: A confirmative one-sided, one-sample Poisson test was used to test whether the mean annualized bleeding rate (ABR) in patients treated prophylactically with Wilate was below the threshold of 29 BEs per patient year (alpha = 2.5%). This threshold corresponds to 50% of the TABR reported in the GENA-01 study (NCT00989196), which observed 58.1 BEs per patient per year. A corresponding two-sided 95% CI for the TABR was also analyzed.p-value: <0.000195% CI: [1.64, 2.76]Poisson test estimate
Secondary
Association Between ABO Blood Type and the FVIII:C Half-life of Wilate (OS Assay)
Analysis of variance (ANOVA) was used in an exploratory sense to assess an association between ABO blood type and the FVIII:C half-life of Wilate. This was analyzed by calculating the mean square in a one-stage assay.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Wilate | Association Between ABO Blood Type and the FVIII:C Half-life of Wilate (OS Assay) | 15.867 Beta coefficient |
p-value: 0.0346ANOVA
Secondary
Association Between VWF:Ag Concentration and the FVIII:C Half-life of Wilate
ANOVA was used in an exploratory sense to assess an association between VWF:Ag with the FVIII:C half-life of Wilate. This was analyzed by calculating the mean square in a one-stage assay.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Wilate | Association Between VWF:Ag Concentration and the FVIII:C Half-life of Wilate | 5.104 Beta coefficient |
p-value: 0.4244ANOVA
Secondary
Efficacy of Wilate in the Treatment of Breakthrough BEs
The proportion of BEs successfully treated with Wilate were documented by the patient (together with the investigator in case of on-site treatments) in the patient diary for all BEs according to a 4-point hemostatic efficacy scale including the four items: 'excellent,' 'good,' moderate,' and 'none', where 'excellent' was defined as Abrupt pain relief and/or unequivocal improvement in objective signs of bleeding within approximately 8 hours after a single injection (best outcome) and 'none' was defined as No improvement within 12 hours, or worsening of symptoms, requiring more than two injections for complete resolution (worst outcome). All efficacy ratings assessed as either 'excellent' or 'good' were considered 'successfully treated.'
Time frame: 6 months
Population: In the PP population, efficacy of Wilate in the treatment of breakthrough BEs was analyzed for all patients experiencing breakthrough BEs (N=24)
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Wilate | Efficacy of Wilate in the Treatment of Breakthrough BEs | Excellent | 16 Number of BEs |
| Wilate | Efficacy of Wilate in the Treatment of Breakthrough BEs | Good | 32 Number of BEs |
| Wilate | Efficacy of Wilate in the Treatment of Breakthrough BEs | Moderate | 9 Number of BEs |
Comparison: Confirmatory statistical testing tested the null hypotheses that the percentage of success is ≤70% (alternative hypothesis: percentage \>70%); the test procedure based on the generalized estimation equation took into account several BEs in one patient as correlated repeated measurements (alpha = 2.5%). Thus, π denotes the proportion of success and the following pair of hypotheses was tested:~H0: π ≤ 0.7 vs. H1: π \> 0.7p-value: 0.009695% CI: [72.13, 92.52]Confirmatory data analysis
Secondary
Immunogenicity of Wilate by Testing for FVIII Inhibitors
FVIII inhibitor activity was determined at each study visit before the injection of Wilate using the modified Bethesda assay (Nijmegen modification).
Time frame: 6 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Wilate | Immunogenicity of Wilate by Testing for FVIII Inhibitors | 0 Participants |
95% CI: [0, 16.11]
Secondary
Incremental in Vivo Recovery (IVR) of Wilate Over Time
The rise in FVIII activity in IU/dl per unit dose administered in IU/kg was determined from all patients at baseline, 3 and 6 months, using the OS assay.
Time frame: Baseline, 3 and 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Wilate | Incremental in Vivo Recovery (IVR) of Wilate Over Time | First PK/non-PK visit | 2.14 kg/dL | Standard Deviation 0.51 |
| Wilate | Incremental in Vivo Recovery (IVR) of Wilate Over Time | 3 months | 2.14 kg/dL | Standard Deviation 0.49 |
| Wilate | Incremental in Vivo Recovery (IVR) of Wilate Over Time | PK/non-PK completion 6 months | 1.97 kg/dL | Standard Deviation 0.64 |
Secondary
Pharmacokinetic (PK) Assessment (Area Under the Curve [AUC] Norm) of FVIII:C
PK assessments of FVIII:C were conducted using the one-stage (OS) assay. The value of the AUCnorm of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study.
Time frame: Initial PK visit (Day -1) and PK study completion visit (6 months); data collected 1 h prior to injection and 15 min, 1 h, 3 h, 6 h, 9 h, 24 h, 30 h and 48 h after the end of injection
Population: AUC divided by dose (IU\*h/dL per IU/kg)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Wilate | Pharmacokinetic (PK) Assessment (Area Under the Curve [AUC] Norm) of FVIII:C | Initial PK | 28.61 IU*h/dL per IU/kg | Standard Deviation 9.31 |
| Wilate | Pharmacokinetic (PK) Assessment (Area Under the Curve [AUC] Norm) of FVIII:C | PK completion 6 months | 30.75 IU*h/dL per IU/kg | Standard Deviation 11.32 |
Secondary
Pharmacokinetic (PK) Assessment (in Vivo Half-Life (t1/2)) of FVIII:C
PK assessments of FVIII:C were conducted using the one-stage (OS) assay. The in vivo half-life of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study.
Time frame: Initial PK assessment (Day -1) and PK study completion visit (6 months); data collected 1 h prior to infusion and 15 min, 1 h, 3 h, 6 h, 9 h, 24 h, 30 h and 48 h after the end of injection
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Wilate | Pharmacokinetic (PK) Assessment (in Vivo Half-Life (t1/2)) of FVIII:C | Initial PK | 10.82 Hours | Standard Deviation 2.5 |
| Wilate | Pharmacokinetic (PK) Assessment (in Vivo Half-Life (t1/2)) of FVIII:C | PK completion 6 months | 11.50 Hours | Standard Deviation 2.3 |
Secondary
Pharmacokinetic (PK) Assessment (Maximum Plasma Concentration [Cmax]) of FVIII:C
PK assessments of FVIII:C were conducted using the one-stage (OS) assay. The maximum plasma concentration of FVIII:C was calculated based on the FVIII:C values measured in the patients participating in the PK study.
Time frame: Initial PK assessment (Day -1) and 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Wilate | Pharmacokinetic (PK) Assessment (Maximum Plasma Concentration [Cmax]) of FVIII:C | Initial PK | 106.70 IU/dL | Standard Deviation 22.45 |
| Wilate | Pharmacokinetic (PK) Assessment (Maximum Plasma Concentration [Cmax]) of FVIII:C | PK completion 6 months | 103.49 IU/dL | Standard Deviation 26.53 |
Secondary
Safety and Tolerability of Wilate by Monitoring Adverse Events (AEs) Throughout the Study
At each (scheduled or unscheduled) study visit, AEs were documented by the investigator throughout the study.
Time frame: 6 months
Population: In the FAS population (N=55), the safety and tolerability of Wilate was analysed for all patients experiencing adverse events (AEs) throughout the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Wilate | Safety and Tolerability of Wilate by Monitoring Adverse Events (AEs) Throughout the Study | Number of Treatment-emergent AEs | 16 Number of adverse events |
| Wilate | Safety and Tolerability of Wilate by Monitoring Adverse Events (AEs) Throughout the Study | Number of AEs | 17 Number of adverse events |
Secondary
Spontaneous Annualized Bleeding Rate (SABR)
The number of spontaneous bleeding events (BEs) was documented by patients in a patient diary (together with the investigator in case of on-site treatments), which was reviewed at each follow-up visit by site personnel.
Time frame: 6 months
Population: The spontaneous annualized bleeding rate (SABR) was calculated for all patients included in the PP population (N=52).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Wilate | Spontaneous Annualized Bleeding Rate (SABR) | 1.51 No. of spontaneous BEs/year (SABR) | Standard Deviation 3.03 |
Comparison: A confirmative one-sided, one-sample Poisson test was used to test whether the mean SABR in patients treated prophylactically with Wilate was below the threshold of 19.1 BEs per patient year (alpha = 2.5%). This threshold corresponds to 50% of the SABR in the GENA-01 study (NCT00989196), which observed 38.2 spontaneous BEs per patient per year. A corresponding two-sided 95% CI for the SABR was also analyzed.p-value: <0.000195% CI: [1.13, 2.08]Poisson test estimate
Secondary
Virus Safety Measured by the Number of Parvovirus B19 Seroconversions Between Baseline (BL) and End of Study
Virus safety was evaluated by taking a plasma sample for parvovirus B19 antibody testing before the first injection of Wilate. All patients negative at screening were tested again at the study completion visit. The number with Parvovirus B19 seroconversions between BL and end of study was recorded.
Time frame: 6 months
Population: In the FAS population (N=55), the viral safety of Wilate was analyzed for all patients at baseline.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Wilate | Virus Safety Measured by the Number of Parvovirus B19 Seroconversions Between Baseline (BL) and End of Study | 0 Participants |
Secondary
Wilate Consumption Data (Average Total Normdose of FVIII IU/kg Per Month of Study) for Prophylaxis
The average consumption of Wilate per month of study (IU/kg) for all patients receiving prophylaxis.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Wilate | Wilate Consumption Data (Average Total Normdose of FVIII IU/kg Per Month of Study) for Prophylaxis | 405.06 IU/kg | Standard Deviation 83.7 |
Other Pre-specified
Efficacy of Wilate in Surgical Prophylaxis
Hemostatic efficacy was assessed at the end of surgery by the surgeon and at end of the postoperative period by the hematologist, using a 4-point hemostatic efficacy scale including the four items: 'excellent' (best possible outcome), 'good', 'moderate' and 'none' (worst outcome). Overall efficacy was assessed by the investigator, taking both the intra and postoperative assessments into account, and using the 'excellent,' 'good,' moderate,' and 'none' scale.
Time frame: 6 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Wilate | Efficacy of Wilate in Surgical Prophylaxis | Excellent | 0 Participants |
| Wilate | Efficacy of Wilate in Surgical Prophylaxis | Good | 1 Participants |
| Wilate | Efficacy of Wilate in Surgical Prophylaxis | Moderate | 0 Participants |
| Wilate | Efficacy of Wilate in Surgical Prophylaxis | None | 0 Participants |