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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| All patients | Experimental | All patients will receive Wilate for prophylactic treatment |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Wilate | Drug |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 6 months |
| Efficacy of Wilate in the Treatment of Breakthrough BEs |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
Inclusion Criteria:
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:
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| Name | Affiliation | Role |
|---|---|---|
| Cristina Solomon, MD | Octapharma | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Specialized Hospital for Active Treatment "Joan Pavel" | Sofia | Bulgaria | ||||
| National Haemophilia Centre |
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| ID | Title | Description |
|---|---|---|
| FG000 | Wilate | A total of 57 patients were enrolled in the study. For the PK assessment (PK population) a single dose of Wilate of 50 ±5 IU/kg BW was administered to 21 patients. For prophylactic treatment, Wilate was administered every 2 to 3 days at a dose of 20-40 IU/kg BW for 6 months. In case of unacceptably frequent spontaneous breakthrough BEs, the dose of Wilate was increased by approximately 5 IU/kg. The dose (and duration) of treatment for BEs was dependent on the location and extent of bleeding and on the clinical condition of the patient; range: 10-50 IU/kg every 12-24 hours or 8-24 hours until resolved. For the surgical prophylaxis population (SURG population), minor surgeries were treated with 15-30 IU/kg every 24 hours, at least 1 day, until healing iwas achieved. Major surgeries were treated with 40-50 IU/kg, repeat injection every 8-24 hours until adequate wound healing, then therapy for at least another 7 days to maintain a FVIII activity of 30% to 60%. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
The safety (SAF) population includes all patients who received at least one administration of Wilate during the study (N=55)
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| ID | Title | Description |
|---|---|---|
| BG000 | Wilate | SAF population (All patients who received at least one administration of Wilate during the study (N=55) |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | The total annualized bleeding rate (TABR) was calculated for all patients included in the PP population (N=52). | Posted | Mean | Standard Deviation | No. of BEs / year (ABR) | 6 months | No. of Bleeding Episodes (BEs) | No. of Bleeding Episodes (BEs) |
|
|
6 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Wilate | SAF population | 0 |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Erysipelas | Infections and infestations | Systematic Assessment | Treatment-emergent adverse event |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Cristina Solomon | Octapharma AG | +41 (0)55 451 21 89 | Cristina.Solomon@octapharma.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jan 16, 2017 | Dec 21, 2020 | Prot_002.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | May 8, 2018 | Dec 21, 2020 | SAP_003.pdf |
| ID | Term |
|---|---|
| D006467 | Hemophilia A |
| ID | Term |
|---|---|
| D025861 | Blood Coagulation Disorders, Inherited |
| D001778 | Blood Coagulation Disorders |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
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| ID | Term |
|---|---|
| D014841 | von Willebrand Factor |
| D005169 | Factor VIII |
| ID | Term |
|---|---|
| D001779 | Blood Coagulation Factors |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
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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.' |
| 6 months |
| 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. | 6 months |
| 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. | 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 |
| 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. | 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 |
| 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. | Initial PK assessment (Day -1) and 6 months |
| 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. | Baseline, 3 and 6 months |
| 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. | 6 months |
| 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. | 6 months |
| 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. | 6 months |
| 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). | 6 months |
| 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. | 6 months |
| 6 months |
| Budapest |
| Hungary |
| Krakowskie Centrum Medyczne | Krakow | Poland |
| Korczowski Bartosz Gabinet Lekarski | Rzeszów | Poland |
| Centrul Medical Unirea -Policlinica Enescu | Bucharest | Romania |
| Barnaul Branch of RAMS hematology center | Barnaul | Russia |
| Federal Scientific Hematology Center | Moscow | Russia |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Weight | Mean | Standard Deviation | kg |
|
| Body mass index (BMI) | Mean | Standard Deviation | kg/m2 |
|
| Blood groups | Count of Participants | Participants |
|
| von Willebrand factor antigen (VWF:Ag) | Plasma VWF:Ag measurements recorded at baseline | Mean | Standard Deviation | IU/dL |
|
| von Willebrand factor activity (VWF:Ac) | Plasma VWF:Ac measurements recorded at baseline | Mean | Standard Deviation | IU/dL |
|
| Previous Factor (F) VIII treatment | Count of Participants | Participants |
|
| Previous annualized bleeding rate (ABR) | Previous ABR is based on the bleeding rate in the 6 months prior to entry into the study. | Mean | Standard Deviation | No. BEs per patient per year |
|
|
| No. of Bleeding Episodes (BEs) |
|
|
|
| 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. | The spontaneous annualized bleeding rate (SABR) was calculated for all patients included in the PP population (N=52). | Posted | Mean | Standard Deviation | No. of spontaneous BEs/year (SABR) | 6 months | No. of BEs | No. of BEs |
|
|
|
|
| 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.' | In the PP population, efficacy of Wilate in the treatment of breakthrough BEs was analyzed for all patients experiencing breakthrough BEs (N=24) | Posted | Count of Units | Number of BEs | 6 months | Number of BEs | Number of BEs |
|
|
|
|
| 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. | Posted | Mean | Standard Deviation | IU/kg | 6 months |
|
|
|
| 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. | AUC divided by dose (IU*h/dL per IU/kg) | Posted | Mean | Standard Deviation | IU*h/dL per IU/kg | 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 |
|
|
|
| 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. | Posted | Mean | Standard Deviation | Hours | 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 |
|
|
|
| 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. | Posted | Mean | Standard Deviation | IU/dL | Initial PK assessment (Day -1) and 6 months |
|
|
|
| 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. | Posted | Mean | Standard Deviation | kg/dL | Baseline, 3 and 6 months |
|
|
|
| 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. | Posted | Number | Beta coefficient | 6 months |
|
|
|
|
| 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. | Posted | Number | Beta coefficient | 6 months |
|
|
|
|
| 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. | In the FAS population (N=55), the safety and tolerability of Wilate was analysed for all patients experiencing adverse events (AEs) throughout the study. | Posted | Number | Number of adverse events | 6 months |
|
|
|
| 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). | Posted | Count of Participants | Participants | 6 months |
|
|
|
|
| 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. | In the FAS population (N=55), the viral safety of Wilate was analyzed for all patients at baseline. | Posted | Number | Participants | 6 months |
|
|
|
| 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. | Posted | Count of Participants | Participants | 6 months |
|
|
|
| 55 |
| 0 |
| 55 |
| 12 |
| 55 |
|
| Nasopharyngitis | Infections and infestations | Systematic Assessment | Treatment-emergent adverse event |
|
| Viral upper respiratory tract infection | Infections and infestations | Systematic Assessment | Treatment-emergent adverse event |
|
| Thrombocytosis | Blood and lymphatic system disorders | Systematic Assessment | Treatment-emergent adverse event |
|
| Seasonal allergy | Immune system disorders | Systematic Assessment | Treatment-emergent adverse event |
|
| Headache | Nervous system disorders | Systematic Assessment | Treatment-emergent adverse event |
|
| Eczema | Skin and subcutaneous tissue disorders | Systematic Assessment | Treatment-emergent adverse event |
|
| Arthralgia | Musculoskeletal and connective tissue disorders | Systematic Assessment | Treatment-emergent adverse event |
|
| Pain | General disorders | Systematic Assessment | Treatment-emergent adverse event |
|
| Limb injury | Injury, poisoning and procedural complications | Systematic Assessment | Treatment-emergent adverse event |
|
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| D020147 | Coagulation Protein Disorders |
| D006474 | Hemorrhagic Disorders |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D001685 |
| Biological Factors |
| D011498 | Protein Precursors |
|
| None |
|