Von Willebrand Disease
Conditions
Brief summary
The WIL-33 study aimed to determine the efficacy, pharmacokinetics, immunogenicity and safety of wilate as routine prophylaxis in up to 12 paediatric patients (eight evaluable) with severe von Willebrand Disease VWD (defined as screening von Willebrand factor ristocetin cofactor activity \[VWF:RCo\] \<20%) under the age of 6 years, over a period of 12 months.
Interventions
DRUGWilate
Wilate is a plasma-derived, stable, highly purified, double virus inactivated concentrate of freeze-dried active VWF and factor VIII (FVIII) prepared from cryoprecipitate and intended for the treatment of patients with VWD and/or haemophilia A
Sponsors
Octapharma
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 5 Years
Healthy volunteers
No
Inclusion criteria
1. Patients aged \<6 years at the time of screening 2. Type 3 (at least four patients), severe type 2 (except 2N) or severe type 1 VWD (any of which with VWF:RCo \<20%) according to medical history, requiring substitution therapy with a VWF-containing product 3. Minimum BW 12.5 kg at the time of screening (for Moldova and Czech Republic, minimum BW 11.0 kg at the time of screening) 4. Voluntarily given, fully informed written and signed consent obtained before any study-related procedures are conducted (obtained from the patient's parent(s) / legal guardian(s))
Exclusion criteria
1. History or current suspicion of VWF or FVIII inhibitors 2. Injection of 1-deamino-8-D-arginine vasopressin (DDAVP) or VWF-containing product within 72 hours prior to inclusion 3. Medical history of a thromboembolic event 4. Platelet count \<100,000/µL at screening (except for VWD type 2B) 5. Patients receiving, or scheduled to receive, immunosuppressant drugs (other than antiretroviral chemotherapy), such as prednisone (equivalent to \>10 mg/day), or similar drugs 6. Treatment with any investigational medicinal product (IMP) in another interventional clinical study currently or within four weeks before enrolment 7. Other coagulation disorders or bleeding disorders 8. Known hypersensitivity to any of the components of the study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Annualised Bleeding Rate (TABR) During Prophylactic Treatment With Wilate. | During 12 months of prophylactic treatment | TABR is defined as the total number of bleeding episodes (BEs) including spontaneous, traumatic, and other bleeds, occurring during the period from the first prophylactic dose of wilate to the study completion visit, divided by the duration (in years) between these two time points. Bleeding episodes that occurred during surgery periods were excluded from the calculation of TABR. Total BEs refers to all bleeding episodes that occurred during the study period, regardless of whether they were treated with wilate or not. Treated BEs are a subset of total BEs comprising of bleeding episodes that were treated with wilate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC) of Wilate for VWF:Ac (VWF:RCo) Over Time | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | Mean AUC of VWF:Ac after PK injection of wilate as measured by chromogenic assay. |
| Area Under the Curve (AUC) of Wilate for FVIII (OS) Over Time | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | Mean AUC of FVIII after PK injection of wilate as measured by chromogenic assay. |
| AUC Normalised for the Administered Dose (AUCnorm) of Wilate for VWF:Ac (VWF:RCo) Over Time | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | Mean AUC of VWF:Ac after PK injection of wilate, normalised for the actual administered dose (IU/kg), over time. AUC norm was measured and reported as \[h\*kg/IU\]/(dL/IU) which could also be reported as h\*kg/dL. |
| AUC Normalised for the Administered Dose (AUCnorm) of Wilate for FVIII:C (OS) Over Time | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | Mean AUC of FVIII after PK injection of wilate, normalised for the actual administered dose (IU/kg), over time. AUC norm was measured and reported as \[h\*kg/IU\]/(dL/IU) which could also be reported as h\*kg/dL. |
| Clearance (CL) of Wilate for VWF:Ac (VWF:RCo) Over Time | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | Mean clearance (CL) of VWF:Ac, measured by ristocetin cofactor assay \[VWF:RCo\]) after PK injection of wilate, calculated as the ratio of dose administered to the area under the plasma concentration-time curve (AUC), over time. Clearance was defined as the rate of drug elimination divided by plasma concentration, giving a volume of plasma from which drug is completely removed per unit of time. |
| Clearance (CL) of Wilate for FVIII:C (OS) Over Time | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | Mean clearance (CL) of FVIII:C, measured by one-stage assay \[OS\]) after PK injection of wilate, calculated as the ratio of dose administered to the area under the plasma concentration-time curve (AUC), over time. |
| Maximum Plasma Concentration (Cmax) of Wilate for VWF:Ac (VWF:RCo) Over Time | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | Mean maximum plasma concentration (Cmax) of VWF:Ac, measured by ristocetin cofactor assay \[VWF:RCo\]) after PK injection of wilate, as determined from the observed peak value in the plasma concentration-time profile. |
| Maximum Plasma Concentration (Cmax) of Wilate for FVIII:C (OS) Over Time | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | Mean maximum plasma concentration (Cmax) of FVIII:C, measured by one-stage assay \[OS\]) after PK injection of wilate, as determined from the observed peak value in the plasma concentration-time profile. |
| Mean Residence Time (MRT) of Wilate for VWF:Ac (VWF:RCo) Over Time | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | Mean residence time (MRT) of VWF:Ac, measured by ristocetin cofactor assay \[VWF:RCo\]) after PK injection of wilate, calculated as the average time a VWF:Ac molecule remains in the body, derived from the ratio of area under the first moment curve (AUMC) to AUC. |
| Mean Residence Time (MRT) of Wilate for FVIII:C (OS) Over Time | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | Mean residence time (MRT) of FVIII:C, measured by one-stage assay \[OS\]) after PK injection of wilate, calculated as the average time a FVIII:C molecule remains in the body, derived from the ratio of area under the first moment curve (AUMC) to AUC. |
| In Vivo Half-life (T1/2) of Wilate for VWF:Ac (VWF:RCo) Over Time | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | Mean in vivo half-life (T1/2) VWF:Ac, measured by ristocetin cofactor assay \[VWF:RCo\]) after PK injection of wilate, calculated as the time required for the plasma concentration to decrease by half during the terminal elimination phase. |
| In Vivo Half-life (T1/2) of Wilate for FVIII:C (OS) Over Time | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | Mean in vivo half-life (T1/2) of FVIII:C, measured by one-stage assay \[OS\]) after PK injection of wilate, calculated as the time required for the plasma concentration to decrease by half during the terminal elimination phase. |
| Time to Reach Maximum Plasma Concentration (Tmax) of Wilate for VWF:Ac (VWF:RCo) Over Time | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | Mean time to reach maximum plasma concentration (Tmax) of VWF:Ac, measured by ristocetin cofactor assay \[VWF:RCo\]) after PK injection of wilate, defined as the time from dosing to the observed peak plasma concentration. |
| Time to Reach Maximum Plasma Concentration (Tmax) of Wilate for FVIII:C (OS) Over Time | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | Mean time to reach maximum plasma concentration (Tmax) of FVIII:C, measured by one-stage assay \[OS\]) after PK injection of wilate, defined as the time from dosing to the observed peak plasma concentration. |
| Volume of Distribution (Vd) of Wilate for VWF:Ac (VWF:RCo) Over Time | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | Mean volume of distribution at steady state (Vd) of VWF:Ac, measured by ristocetin cofactor assay \[VWF:RCo\]) after PK injection of wilate, calculated as clearance (CL) multiplied by mean residence time (MRT). |
| Volume of Distribution (Vd) of Wilate for FVIII:C (OS) Over Time | At baseline, 15 minutes, 3, 9, 24, 48 and 72 hours after dosing of 80 IU/kg BW wilate | Mean volume of distribution at steady state (Vd) of FVIII:C, measured by one-stage assay \[OS\]) after PK injection of wilate, calculated as clearance (CL) multiplied by mean residence time (MRT). |
| Incremental In-vivo Recovery (IVR) of Wilate for VWF:Ac (VWF:RCo) Over Time | Measures were taken at the following timepoints: baseline and 1, 2, 3, 6, 9, and 12 months of treatment with IVR values reported at baseline and 12 months. | Mean incremental in vivo recovery (IVR) of VWF:Ac, measured by ristocetin cofactor assay \[VWF:RCo\]) after PK injection of wilate, calculated as the increase in plasma VWF:Ac concentration per IU/kg of wilate administered. |
| Incremental In-vivo Recovery (IVR) of Wilate for FVIII:C (OS) Over Time | Measures were taken at the following timepoints: baseline and 1, 2, 3, 6, 9, and 12 months of treatment with IVR values reported at baseline and 12 months. | Mean incremental in vivo recovery (IVR) of FVIII:C, measured by one-stage assay \[OS\]) after PK injection of wilate, calculated as the increase in plasma FVIII:C concentration per IU/kg of wilate administered. |
| Efficacy of Wilate Measured by the Proportion of BEs Successfully Treated With Wilate | Up to 12 months of treatment | Proportion of BEs successfully treated with wilate, as assessed using a predefined 4-point ordinal haemostatic efficacy scale. Each BE was rated at the end of treatment as "excellent", "good", "moderate", or "none" based on the time to bleeding cessation and the dose required. A BE is considered successfully treated if the efficacy rating is "excellent" (bleeding stopped within 3 days for minor bleeds, within 7 days for major bleeds, or within 10 days for gastrointestinal bleeds) or "good" (bleeding stopped, but time and/or dose slightly exceeded expectations). The outcome is reported as the percentage of BEs with a rating of "excellent" or "good" out of all treated BEs |
| The Overall Efficacy of Wilate in Perioperative Prophylaxis Against Excessive Bleeding as Assessed at the End of the Postoperative Period by the Responsible Treating Investigator | Up to 12 months of treatment | Overall efficacy of wilate in perioperative prophylaxis against excessive bleeding, as assessed at the end of the postoperative period by the responsible treating investigator using a predefined 4-point ordinal haemostatic efficacy scale. The assessment is based on the presence or absence of postoperative bleeding or oozing, the need for additional dosing, and the ability to control bleeding with wilate. Excellent: No postoperative bleeding or oozing not due to surgical complications; all postoperative bleeding due to complications controlled with wilate as anticipated for the procedure. Good: No postoperative bleeding or oozing not due to surgical complications; control of postoperative bleeding due to complications required increased dosing or additional injections of wilate not originally anticipated. Moderate: Some postoperative bleeding or oozing not due to surgical complications; control required increased dosing or additional injections of wilate not originally anticipated |
| Consumption of Wilate for Prophylactic Treatment | Up to 12 months of treatment | Mean dose of wilate administered for routine prophylactic treatment, reported as (a) mean dose per injection (IU/kg) and (b) mean dose per week (IU/kg). Dose per injection is calculated as the total amount of wilate (IU) administered per injection divided by the patient's body weight (kg). Dose per week was calculated as the total amount of wilate (IU) administered for prophylaxis in a week, divided by the patient's body weight (kg). Both measures were averaged across all prophylactic infusions during the study period |
| Consumption of Wilate for the Treatment of BEs (On-demand Treatment) | Up to 12 months of treatment | Mean dose of wilate administered for the on-demand treatment of BEs, reported as (a) mean dose per BE (IU/kg) and (b) mean dose per injection (IU/kg). Dose per BE is calculated as the total amount of wilate (IU) administered per BE treatment divided by the patient's body weight (kg). Dose per injection is calculated as the total amount of wilate (IU) administered for BE treatment in a week, divided by the patient's body weight (kg). Both measures are averaged across all treated BEs during the study period |
| Consumption of Wilate During Surgical Prophylaxis | Up to 12 months of treatment | Mean dose of wilate administered for surgical prophylaxis, reported as dose per exposure day (ED) in IU/kg. Dose per exposure day is calculated as the total amount of wilate (IU) administered for surgical prophylaxis on each day, divided by the patient's body weight (kg). The measure is averaged across all exposure days during the perioperative period |
| Number of Participants With Detectable Inhibitory Antibodies Against VWF and/or FVIII | Up to 12 months of treatment | Number of patients with detectable inhibitory antibodies to von Willebrand factor (VWF) and factor VIII (FVIII) during the study testing. Inhibitor testing is performed at baseline, every 3 months, and at any time if inhibitor development is suspected. |
| Number of Participants With Detectable Thromboembolic Events | Up to 12 months of treatment | Incidence of thromboembolic events, defined as the proportion of patients who experience one or more thromboembolic events (such as deep vein thrombosis, pulmonary embolism, or other clinically relevant thromboses) during the study period. Thromboembolic events are monitored and recorded as adverse events throughout the study, and are confirmed by clinical assessment and/or diagnostic imaging as appropriate. The outcome is reported as the number and percentage of patients with at least one thromboembolic event during the study |
| Change in Haemophilia Joint Health Score | At baseline and at 12 months of treatment | Change from baseline in the Haemophilia Joint Health Score (HJHS) total score, assessed at baseline and at the end of the study (12 months). The HJHS is a validated clinical tool used to evaluate joint health in patients with bleeding disorders, measured over a scale of 0-124, with higher scores indicating worse joint health. This score is comprised of the assessments of 6 joints according to 8 criteria (each joint is scored from 0 to 20, giving a possible assessment range for all joints of 0 to 120) plus the Global Gait Score (measured from 0 to 4). The outcome is reported as the mean change in total HJHS score from baseline to study completion for each participant. An increase (positive value) indicates an increase in HJHS over the course of the study and worsening of joint health. A decrease (negative value) reflects a reduction in HJHS over the study duration and improvements in joint health. Assessments are performed by trained investigators using the standard HJHS protocol. |
Countries
Czechia, Germany, Moldova, North Macedonia, Russia, Ukraine, United States
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 2.5 years STANDARD_DEVIATION 1.2 |
| Blood Group A | 4 Participants |
| Blood Group AB | 2 Participants |
| Blood Group B | 2 Participants |
| Blood Group O | 3 Participants |
| Blood Group Unknown | 1 Participants |
| Family history of VWD No | 6 Participants |
| Family history of VWD Yes | 6 Participants |
| FVIII inhibitor history No | 12 Participants |
| FVIII inhibitor history Yes | 0 Participants |
| Race/Ethnicity, Customized Arabian | 2 Participants |
| Race/Ethnicity, Customized White | 10 Participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 6 Participants |
| VWD type Type 2 | 4 Participants |
| VWD type Type 3 | 8 Participants |
| VWF inhibitor history No | 12 Participants |
| VWF inhibitor history Yes | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 12 |
| other Total, other adverse events | 10 / 12 |
| serious Total, serious adverse events | 4 / 12 |
Outcome results
None listed