Clinical Trial Page
Clinical Trial Results:
A Prospective, Phase 3, Open-label, International Multicenter Study on Efficacy and Safety of Prophylaxis with rVWF in Severe von Willebrand Disease
| Summary | |
EudraCT number | 2016-001478-14 |
Trial protocol | GB IT CZ NL ES DE FI FR |
Global end of trial date | 06 Jul 2020 |
| Results information | |
Results version number | v1(current) |
This version publication date | 21 Jul 2021 |
First version publication date | 21 Jul 2021 |
Other versions | |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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| Trial identification | |||
Sponsor protocol code | 071301 | ||
| Additional study identifiers | |||
ISRCTN number | - | ||
US NCT number | NCT02973087 | ||
WHO universal trial number (UTN) | - | ||
| Sponsors | |||
Sponsor organisation name | Takeda | ||
Sponsor organisation address | 95 Hayden Avenue, Lexington, United States, MA 02421 | ||
Public contact | Study Director, Takeda, TrialDisclosures@takeda.com | ||
Scientific contact | Study Director, Takeda, TrialDisclosures@takeda.com | ||
| Paediatric regulatory details | |||
Is trial part of an agreed paediatric investigation plan (PIP) | No | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? | No | ||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? | No | ||
| Results analysis stage | |||
Analysis stage | Final | ||
Date of interim/final analysis | 06 Jul 2020 | ||
Is this the analysis of the primary completion data? | No | ||
Global end of trial reached? | Yes | ||
Global end of trial date | 06 Jul 2020 | ||
Was the trial ended prematurely? | No | ||
| General information about the trial | |||
Main objective of the trial | The main objective of this study was to prospectively evaluate the annualised bleeding rate (ABR) for spontaneous bleeding episodes while on prophylactic treatment with recombinant von Willebrand factor (rVWF) and to compare it to the subject’s historical ABR for spontaneous bleeding episodes. | ||
Protection of trial subjects | The study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and in compliance with all applicable industry regulations, International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6 (1996), European Union (EU) Directive 2001/20/EC, as well as all applicable national and local laws and regulations. | ||
Background therapy | - | ||
Evidence for comparator | - | ||
Actual start date of recruitment | 16 Nov 2017 | ||
Long term follow-up planned | No | ||
Independent data monitoring committee (IDMC) involvement? | Yes | ||
| Population of trial subjects | |||
Number of subjects enrolled per country | |||
Country: Number of subjects enrolled | Canada: 1 | ||
Country: Number of subjects enrolled | Russian Federation: 4 | ||
Country: Number of subjects enrolled | Turkey: 7 | ||
Country: Number of subjects enrolled | United States: 1 | ||
Country: Number of subjects enrolled | France: 2 | ||
Country: Number of subjects enrolled | Germany: 2 | ||
Country: Number of subjects enrolled | Italy: 3 | ||
Country: Number of subjects enrolled | Netherlands: 1 | ||
Country: Number of subjects enrolled | Spain: 2 | ||
Worldwide total number of subjects | 23 | ||
EEA total number of subjects | 10 | ||
Number of subjects enrolled per age group | |||
In utero | 0 | ||
Preterm newborn - gestational age | 0 | ||
Newborns (0-27 days) | 0 | ||
Infants and toddlers (28 days-23 months) | 0 | ||
Children (2-11 years) | 0 | ||
Adolescents (12-17 years) | 0 | ||
Adults (18-64 years) | 20 | ||
From 65 to 84 years | 3 | ||
85 years and over | 0 | ||
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| Recruitment | ||||||||||||||||||||||
Recruitment details | This study was conducted at 32 sites in the United States, Canada, France, Germany, Italy, Netherlands, Russia, Spain and Turkey between 16 November 2017 (first subject first visit) and 06 July 2020 (last subject last visit). | |||||||||||||||||||||
| Pre-assignment | ||||||||||||||||||||||
Screening details | A total of 29 subjects were screened, out of which 6 subjects were screen failures and 23 subjects were grouped into 2 cohorts: Prior On-demand and Switch (based on the previous von Willebrand disease [VWD] treatment they received prior to the study) and received prophylactic treatment with recombinant von Willebrand factor (rVWF). | |||||||||||||||||||||
| Period 1 | ||||||||||||||||||||||
Period 1 title | Overall Study (overall period) | |||||||||||||||||||||
Is this the baseline period? | Yes | |||||||||||||||||||||
Allocation method | Not applicable | |||||||||||||||||||||
Blinding used | Not blinded | |||||||||||||||||||||
| Arms | ||||||||||||||||||||||
Are arms mutually exclusive | Yes | |||||||||||||||||||||
| Arm title | Prior On-demand Subjects | |||||||||||||||||||||
Arm description | Subjects who had taken only on-demand von Willebrand factor (VWF) prior to the current study received rVWF (vonicog alpha) initial prophylactic treatment at a dose range of 50 plus minus (+/- ) 10 international unit per kilogram (IU/kg), intravenous infusion, twice per week for a planned period of 12 months. Dose escalation to higher dose (up to 80 IU/kg per infusion) or frequency (up to 3 times a week) was based on medical indication and investigator judgment. During this prophylactic treatment period, any breakthrough bleeding episodes requiring replacement therapy with VWF concentrate was treated with rVWF with or without ADVATE (recombinant Factor VIII [rFVIII]); the dose was determined according to the bleeding type and severity, and was adjusted based on the subject’s clinical response. | |||||||||||||||||||||
Arm type | Experimental | |||||||||||||||||||||
Investigational medicinal product name | Recombinant von Willebrand factor (rVWF) | |||||||||||||||||||||
Investigational medicinal product code | ||||||||||||||||||||||
Other name | vonicog alpha | |||||||||||||||||||||
Pharmaceutical forms | Infusion | |||||||||||||||||||||
Routes of administration | Intravenous use | |||||||||||||||||||||
Dosage and administration details | Subjects received an initial prophylactic dose of 50 +/- 10 IU/kg, intravenous, infusion, twice per week for up to 12 months. | |||||||||||||||||||||
Investigational medicinal product name | Recombinant Factor VIII (rFVIII) | |||||||||||||||||||||
Investigational medicinal product code | ||||||||||||||||||||||
Other name | octocog alfa/ADVATE | |||||||||||||||||||||
Pharmaceutical forms | Infusion | |||||||||||||||||||||
Routes of administration | Intravenous use | |||||||||||||||||||||
Dosage and administration details | Subjects received rFVIII (octocog alfa/ADVATE), intravenous, infusion for treatment of bleeding episode, if needed. | |||||||||||||||||||||
| Arm title | Switch Subjects | |||||||||||||||||||||
Arm description | Subjects who had taken prophylactic treatment with plasma derived VWF product (pdVWF) prior to current study and switched to prophylaxis with rVWF (vonicog alpha) during the study for a planned period of 12 months; received rVWF twice weekly at an initial prophylactic dose of +/- 10 percent (%) of VWF in the pdVWF weekly dose received prior to this study. Dosing with rVWF up to 80 IU/kg per infusion or at a frequency up to 3 times a week or once a week were allowed depending on the total weekly dose and the dosing regimen used in their previous pdVWF prophylaxis regimen and based on medical indication and investigator judgment. During this prophylactic treatment period, any breakthrough bleeding episodes requiring replacement therapy with VWF concentrate was treated with rVWF with or without ADVATE (rFVIII); the dose was determined according to the bleeding type and severity, and was adjusted based on the subject’s clinical response. | |||||||||||||||||||||
Arm type | Experimental | |||||||||||||||||||||
Investigational medicinal product name | Recombinant von Willebrand factor (rVWF) | |||||||||||||||||||||
Investigational medicinal product code | ||||||||||||||||||||||
Other name | vonicog alpha | |||||||||||||||||||||
Pharmaceutical forms | Infusion | |||||||||||||||||||||
Routes of administration | Intravenous use | |||||||||||||||||||||
Dosage and administration details | Subjects received rVWF at an initial prophylactic dose of +/- 10% of weekly pdVWF dose received prior to this study, intravenous, infusion, twice per week for up to 12 months. | |||||||||||||||||||||
Investigational medicinal product name | Recombinant Factor VIII (rFVIII) | |||||||||||||||||||||
Investigational medicinal product code | ||||||||||||||||||||||
Other name | octocog alfa/ADVATE | |||||||||||||||||||||
Pharmaceutical forms | Infusion | |||||||||||||||||||||
Routes of administration | Intravenous use | |||||||||||||||||||||
Dosage and administration details | Subjects received rFVIII (octocog alfa/ADVATE), intravenous, infusion for treatment of bleeding episode, if needed. | |||||||||||||||||||||
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| Baseline characteristics reporting groups | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title | Prior On-demand Subjects | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description | Subjects who had taken only on-demand von Willebrand factor (VWF) prior to the current study received rVWF (vonicog alpha) initial prophylactic treatment at a dose range of 50 plus minus (+/- ) 10 international unit per kilogram (IU/kg), intravenous infusion, twice per week for a planned period of 12 months. Dose escalation to higher dose (up to 80 IU/kg per infusion) or frequency (up to 3 times a week) was based on medical indication and investigator judgment. During this prophylactic treatment period, any breakthrough bleeding episodes requiring replacement therapy with VWF concentrate was treated with rVWF with or without ADVATE (recombinant Factor VIII [rFVIII]); the dose was determined according to the bleeding type and severity, and was adjusted based on the subject’s clinical response. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title | Switch Subjects | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description | Subjects who had taken prophylactic treatment with plasma derived VWF product (pdVWF) prior to current study and switched to prophylaxis with rVWF (vonicog alpha) during the study for a planned period of 12 months; received rVWF twice weekly at an initial prophylactic dose of +/- 10 percent (%) of VWF in the pdVWF weekly dose received prior to this study. Dosing with rVWF up to 80 IU/kg per infusion or at a frequency up to 3 times a week or once a week were allowed depending on the total weekly dose and the dosing regimen used in their previous pdVWF prophylaxis regimen and based on medical indication and investigator judgment. During this prophylactic treatment period, any breakthrough bleeding episodes requiring replacement therapy with VWF concentrate was treated with rVWF with or without ADVATE (rFVIII); the dose was determined according to the bleeding type and severity, and was adjusted based on the subject’s clinical response. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| End points reporting groups | |||
Reporting group title | Prior On-demand Subjects | ||
Reporting group description | Subjects who had taken only on-demand von Willebrand factor (VWF) prior to the current study received rVWF (vonicog alpha) initial prophylactic treatment at a dose range of 50 plus minus (+/- ) 10 international unit per kilogram (IU/kg), intravenous infusion, twice per week for a planned period of 12 months. Dose escalation to higher dose (up to 80 IU/kg per infusion) or frequency (up to 3 times a week) was based on medical indication and investigator judgment. During this prophylactic treatment period, any breakthrough bleeding episodes requiring replacement therapy with VWF concentrate was treated with rVWF with or without ADVATE (recombinant Factor VIII [rFVIII]); the dose was determined according to the bleeding type and severity, and was adjusted based on the subject’s clinical response. | ||
Reporting group title | Switch Subjects | ||
Reporting group description | Subjects who had taken prophylactic treatment with plasma derived VWF product (pdVWF) prior to current study and switched to prophylaxis with rVWF (vonicog alpha) during the study for a planned period of 12 months; received rVWF twice weekly at an initial prophylactic dose of +/- 10 percent (%) of VWF in the pdVWF weekly dose received prior to this study. Dosing with rVWF up to 80 IU/kg per infusion or at a frequency up to 3 times a week or once a week were allowed depending on the total weekly dose and the dosing regimen used in their previous pdVWF prophylaxis regimen and based on medical indication and investigator judgment. During this prophylactic treatment period, any breakthrough bleeding episodes requiring replacement therapy with VWF concentrate was treated with rVWF with or without ADVATE (rFVIII); the dose was determined according to the bleeding type and severity, and was adjusted based on the subject’s clinical response. | ||
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End point title | Ratio of Annualized Bleeding Rate (ABR) (On-study ABR / Historical ABR) for Spontaneous Bleeding Episodes (BEs) Assessed by Investigator During Prophylactic Treatment With rVWF Through Month 12 [1] | ||||||||||||
End point description | ABR for treated spontaneous BEs while on prophylactic treatment with rVWF through Month 12 treatment period/observation period (in years), where an observation period = (date of completion/termination – date of first dose + 1)/365.2425. BEs occurred at the same anatomical location with the same etiology within 24 hours after onset of first bleed were considered single BE. BEs occurred at multiple locations related to same injury were considered as single BE. Observation period for historical BEs was 365 days prior to first dose of study drug. On-study observation period started from first administration of study drug and continuing through the date of completion/discontinuation from study. The comparison of the two ABRs (on-study and historical) for spontaneous BEs (not related to trauma) during prophylactic treatment with rVWF was reported as a ratio of mean ABRs (on-study ABR/historical ABR). Full analysis set (FAS) composed of all subjects who received prophylactic IP treatment. | ||||||||||||
End point type | Primary | ||||||||||||
End point timeframe | Up to 12 months | ||||||||||||
| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||||||
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| No statistical analyses for this end point | |||||||||||||
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End point title | Percentage of Prior On-demand Subjects Achieved Spontaneous ABR Percent Reduction Success Through Month 12 [2] | ||||||||
End point description | For prior on-demand subjects, spontaneous ABR percent reduction success was defined as at least 25% reduction of the ABR for treated spontaneous (not related to trauma) BEs during the first 12 months of rVWF (vonicog alfa) prophylactic relative to the subject’s own historical treated spontaneous ABR. Percentage of subjects with ABR percent reduction success for on-demand cohort was reported. FAS composed of all subjects who received prophylactic IP treatment. This end point was analyzed only for prior on-demand subjects treated for spontaneous BEs. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | Up to 12 months | ||||||||
| Notes [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
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| No statistical analyses for this end point | |||||||||
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End point title | Percentage of Switch Subjects With Spontaneous ABR Preservation Success Through Month 12 [3] | ||||||||
End point description | For switch subjects, spontaneous ABR preservation success was defined as achieving an ABR for treated spontaneous BEs during 12 months of rVWF (vonicog alfa) prophylaxis that was no greater than the subject’s own historical ABR for treated spontaneous BEs during prophylactic treatment with pdVWF. Percentage of subjects with ABR preservation success in switch cohort was reported. FAS composed of all subjects who received prophylactic IP treatment. This end point was analysed only for switch subjects treated for spontaneous BEs. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | Up to 12 months | ||||||||
| Notes [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
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| No statistical analyses for this end point | |||||||||
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End point title | Number of Subjects Based on Categorized Spontaneous ABR (sABR) Through Month 12 | |||||||||||||||||||||||||||||||||
End point description | The sABR was the number of spontaneous bleeds divided by the observation period in years, where an observation period = (date of completion/termination–date of first dose+1)/365.2425.sABR was categorized based on number of BEs as 0, greater than (>) 0 through 2,>2 through 5,>5 during the prophylactic treatment with rVWF (vonicog alfa) through 12 months. Bleeding at multiple locations related to the same injury was counted as single bleeding episode. BEs of unknown cause were counted as spontaneous bleeds. Observation period for historical BEs was 365 days prior to first dose of study drug. The baseline sABR for treated BEs was based on historical BE data and on-study sABR was based on treated spontaneous BEs during prophylaxis with rVWF through Month 12. On-study observation period started on the day of first administration of study drug continuing through the date of completion/discontinuation from study. Number of participants based on categorized sABR was calculated and reported. | |||||||||||||||||||||||||||||||||
End point type | Secondary | |||||||||||||||||||||||||||||||||
End point timeframe | Baseline up to 12 months | |||||||||||||||||||||||||||||||||
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||
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End point title | Total Number of Infusions Administered Per Subject During Prophylactic Treatment With rVWF Through Month 12 | ||||||||||||
End point description | For each subject, the total number of infusions was counted as the total number of unique infusions of rVWF which were administered between the dates of informed consent and termination from the study, inclusive, regardless of the date and time of administration. The total number of infusions administered during the study was entered in electronic case record form (eCRF) and recorded in ERT system. Total number of infusions administered per subject during prophylactic treatment With rVWF through 12 months was calculated. FAS composed of all subjects who received prophylactic IP treatment. | ||||||||||||
End point type | Secondary | ||||||||||||
End point timeframe | Up to 12 months | ||||||||||||
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| No statistical analyses for this end point | |||||||||||||
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End point title | Average Number of Infusions per Week per Subject During Prophylactic Treatment With rVWF Through Month 12 | ||||||||||||
End point description | Average number of infusions per week per subject during prophylactic treatment With rVWF through 12 months was calculated. FAS composed of all subjects who received prophylactic IP treatment. | ||||||||||||
End point type | Secondary | ||||||||||||
End point timeframe | Up to 12 months | ||||||||||||
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| No statistical analyses for this end point | |||||||||||||
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End point title | Total Weight Adjusted Consumption of rVWF per Subject During Prophylactic Treatment Through Month 12 | ||||||||||||
End point description | For each subject, the body weight-adjusted dose (IU/kg) was derived as the number of units of rVWF infused (IU) divided by the last available body weight (kilogram [kg]) prior to the infusion. Total weight adjusted consumption of rVWF (vonicog alfa) per subject during prophylactic treatment was reported. FAS composed of all subjects who received prophylactic IP treatment. | ||||||||||||
End point type | Secondary | ||||||||||||
End point timeframe | Up to 12 months | ||||||||||||
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| No statistical analyses for this end point | |||||||||||||
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End point title | Percentage of Treated Spontaneous BEs by Location of Bleeding While on Prophylactic Treatment With rVWF Through Month 12 | |||||||||||||||||||||||||||
End point description | Percentage of treated spontaneous BEs by location of bleeding (for example: oral and other mucosa, menorrhagia, hemarthrosis, etc.) while on prophylactic treatment with rVWF was reported. FAS composed of all subjects who received prophylactic IP treatment. | |||||||||||||||||||||||||||
End point type | Secondary | |||||||||||||||||||||||||||
End point timeframe | Up to 12 months | |||||||||||||||||||||||||||
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||
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End point title | Number of Subjects Reporting one or More Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | |||||||||||||||
End point description | An AE is defined as any untoward medical occurrence in a subject administered IP that does not necessarily have a causal relationship with the treatment. TEAEs were events which occurred on or after the date and time of administration of the first dose of study medication. TEAEs included both serious AEs and non-serious AEs. Number of subjects with TEAEs and serious TEAEs were reported. SAS composed of all subjects who received any amount of IP (rVWF, vonicog alpha). | |||||||||||||||
End point type | Secondary | |||||||||||||||
End point timeframe | From first dose of study drug up to end of study (approximately 32 months) | |||||||||||||||
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| No statistical analyses for this end point | ||||||||||||||||
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End point title | Number of Subjects Based on Severity of TEAEs | ||||||||||||||||||
End point description | An AE is defined as any untoward medical occurrence in a subject administered IP that does not necessarily have a causal relationship with the treatment. TEAEs were events which occurred on or after the date and time of administration of the first dose of study medication. TEAEs included both serious AEs and non-serious AEs. Severity of TEAEs was determined by following definitions: Mild: No limitation of usual activities; Moderate: Some limitation of usual activities and may required therapeutic intervention; Severe: Inability to carry out usual activities with sequelae, which required therapeutic intervention. Subjects were counted by considering the maximum severity of TEAEs. SAS composed of all subjects who received any amount of IP (rVWF, vonicog alpha). | ||||||||||||||||||
End point type | Secondary | ||||||||||||||||||
End point timeframe | From first dose of study drug up to end of study (approximately 32 months) | ||||||||||||||||||
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title | Number of Subjects With TEAEs Based Causality | ||||||||||||
End point description | An AE was defined as any untoward medical occurrence in a subject administered IP that does not necessarily have a causal relationship with the treatment. TEAEs were events which occurred on or after the date and time of administration of the first dose of study medication. TEAEs included both serious AEs and non-serious AEs. For each AE, the investigator assessed the causal relationship between the IP and the AE based on clinical expertise and judgment according to the following circumstances of the AE: Not related, Unlikely related, Possibly related, or Probably related. A related TEAE was defined as any TEAE indicated as 'possibly related' or 'probably related'. Number of subjects with TEAEs based causality was reported. SAS composed of all subjects who received any amount of IP (rVWF, vonicog alpha). | ||||||||||||
End point type | Secondary | ||||||||||||
End point timeframe | From first dose of study drug up to end of study (approximately 32 months) | ||||||||||||
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| No statistical analyses for this end point | |||||||||||||
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End point title | Number of Subjects With Thromboembolic Events | |||||||||
End point description | Thromboembolism defined as formation in a blood vessel of a clot (thrombus) that breaks loose and carried by the blood stream and could plug another vessel. Number of participants with thromboembolic events as TEAEs of special interest was reported. A broad standard search query approach was used (broad SMQ) to identify all potential thromboembolic events of interest which were then medically assessed. Number of subjects with thromboembolic events as TEAEs of special interest was reported. SAS composed of all subjects who received any amount of IP (rVWF, vonicog alpha). | |||||||||
End point type | Secondary | |||||||||
End point timeframe | From first dose of study drug up to end of study (approximately 32 months) | |||||||||
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| No statistical analyses for this end point | ||||||||||
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End point title | Number of Subjects With Hypersensitivity Reactions | |||||||||
End point description | Hypersensitivity (also called hypersensitivity reaction or intolerance) defined as undesirable reactions produced by the normal immune system, including allergies and autoimmunity. Potential hypersensitivity events were identified by broad search criteria and then medically assessed. Number of subjects with hypersensitivity reactions as TEAEs of special interest was calculated. SAS composed of all subjects who received any amount of IP (rVWF, vonicog alpha). | |||||||||
End point type | Secondary | |||||||||
End point timeframe | From first dose of study drug up to end of study (approximately 32 months) | |||||||||
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| No statistical analyses for this end point | ||||||||||
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End point title | Number of Subjects who Developed Neutralizing Antibodies to von Willebrand Factor (rVWF) and Factor VIII (FVIII) | |||||||||
End point description | Three functional VWF assays for von Willebrand factor collagen binding (VWF:CB), von Willebrand factor: Ristocetin Cofactor (VWF:RCo) and von Willebrand factor VIII B (VWF:FVIIIB) were used to test the presence of neutralizing anti-VWF antibodies. Neutralizing antibodies to VWF:RCo, VWF:CB and VWF:FVIIIB activities was measured by assays based on the Bethesda assay established for quantitative analysis of FVIII inhibitors (Nijmegen modification of the Bethesda assay). Only confirmed neutralizing anti -VWF antibodies were considered inhibitors. Number of subjects who developed neutralizing antibodies to rVWF and FVIII were assessed. SAS composed of all subjects who received any amount of IP (rVWF, vonicog alpha). | |||||||||
End point type | Secondary | |||||||||
End point timeframe | Baseline through Month 12 | |||||||||
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| No statistical analyses for this end point | ||||||||||
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End point title | Number of Subjects who Developed of Total Binding Antibodies to von Willebrand factor (rVWF) and Factor VIII (FVIII) | |||||||||
End point description | The presence of total binding anti-VWF antibodies was determined by an enzyme-linked immunosorbent assay (ELISA) employing polyclonal anti-human Immunoglobulin (Ig) antibodies (IgG, IgM and IgA). Binding antibodies against FVIII was analyzed using a proprietary enzyme immunoassay. Number of subjects who developed of total binding antibodies to rVWF and FVIII was assessed. SAS composed of all subjects who received any amount of IP (rVWF, vonicog alpha). | |||||||||
End point type | Secondary | |||||||||
End point timeframe | Baseline through Month 12 | |||||||||
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| No statistical analyses for this end point | ||||||||||
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End point title | Number of Subjects who Developed Binding Antibodies to Chinese Hamster Ovary (CHO) proteins, Mouse Immunoglobulin G (IgG) and/or rFurin | |||||||||
End point description | Total Ig antibodies (IgG, IgA, IgM) against CHO protein and human furin was analyzed using ELISA. For detection and quantification of IgG antibodies originating from human plasma that were directed against mouse-IgG (HAMA: human anti- mouse antibodies) was assessed using ELISA (Medac, Hamburg, Germany). Number of subjects who developed binding antibodies to CHO proteins, Mouse IgG and/or rFurin was assessed. SAS composed of all subjects who received any amount of IP (rVWF, vonicog alpha). | |||||||||
End point type | Secondary | |||||||||
End point timeframe | Baseline through Month 12 | |||||||||
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| No statistical analyses for this end point | ||||||||||
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End point title | Number of Subjects With Clinically Significant Change From Baseline in Vital Signs | |||||||||
End point description | Vital signs included blood pressure (systolic and diastolic), pulse rate, respiratory rate and body temperature. Number of subjects with clinically significant change from baseline in vital signs was assessed. SAS composed of all subjects who received any amount of IP (rVWF, vonicog alpha). | |||||||||
End point type | Secondary | |||||||||
End point timeframe | Baseline up to end of study (approximately 32 months) | |||||||||
| ||||||||||
| No statistical analyses for this end point | ||||||||||
| ||||||||||
End point title | Number of Subjects With Clinically Significant Change From Baseline in Clinical Laboratory Parameters | |||||||||
End point description | Clinical laboratory parameters included hematology and clinical chemistry assessments. Number of subjects with clinically significant change from baseline in clinical laboratory parameters was assessed. SAS composed of all subjects who received any amount of IP (rVWF, vonicog alpha). | |||||||||
End point type | Secondary | |||||||||
End point timeframe | Baseline up to end of study (approximately 32 months) | |||||||||
| ||||||||||
| No statistical analyses for this end point | ||||||||||
| |||||||||
End point title | Pharmacokinetic (PK) Assessment: Incremental Recovery (IR) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity [4] | ||||||||
End point description | IR at the maximum plasma concentration of VWF:RCo activity at initial PK assessment was reported. Unit of measure: International Units per deciliter/International Units per kilogram ([IU/dL]/[IU/kg]). PK full analysis set (PKFAS) composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Incremental Recovery (IR) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity [5] | ||||||||
End point description | IR based on VWF:Ag activity at initial PK assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Incremental Recovery (IR) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity [6] | ||||||||
End point description | IR at the maximum plasma concentration of VWF:CB activity at initial PK assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Terminal half-life (T1/2) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity [7] | ||||||||
End point description | T1/2 defined as the time in hours required for the concentration of the drug to reach half of its original value. T1/2 based on VWF:Rco activity at initial PK assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Terminal Half-life (T1/2) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity [8] | ||||||||
End point description | T1/2 defined as the time in hours required for the concentration of the drug to reach half of its original value. T1/2 based on VWF:Ag activity at initial PK assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Terminal Half-life (T1/2) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity [9] | ||||||||
End point description | T1/2 defined as the time in hours required for the concentration of the drug to reach half of its original value. T1/2 based on VWF:CB activity at initial PK assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Mean Residence Time (MRT) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity [10] | ||||||||
End point description | MRT was calculated as (AUMC0-∞/AUC0-∞) – T1/2 where T1 represented the time duration of infusion, where AUMC represented the area under the first moment curve. MRT based on VWF:Rco activity at initial PK assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Mean Residence Time (MRT) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity [11] | ||||||||
End point description | MRT was calculated as (AUMC0-∞/AUC0-∞) – T1/2 where T1 represented the time duration of infusion, where AUMC represented the area under the first moment curve. MRT based on VWF:Ag activity at initial PK assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Mean Residence Time (MRT) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity [12] | ||||||||
End point description | MRT was calculated as (AUMC0-∞/AUC0-∞) – T1/2 where T1 represented the time duration of infusion, where AUMC represented the area under the first moment curve. MRT based on VWF:CB activity at initial PK assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity [13] | ||||||||
End point description | AUC0-∞ based on VWF:Rco activity at initial PK assessment was reported. Unit of measure: International Units*hour per deciliter (IU*h/dL). PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity [14] | ||||||||
End point description | AUC0-∞ based on VWF:Ag activity at initial PK assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Area Under the Plasma Concentration Versus Time Curve From Time 0 Extrapolated to Infinity (AUC0-∞) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity [15] | ||||||||
End point description | AUC0-∞ based on VWF:CB activity at initial PK assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Last Measurable Concentration (AUC0-tlast) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity [16] | ||||||||
End point description | AUC0-tlast based on VWF:Rco activity at initial PK assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Last Measurable Concentration (AUC0-tlast) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity [17] | ||||||||
End point description | AUC0-tlast based on VWF:Ag activity at initial PK assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Last Measurable Concentration (AUC0-tlast) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity [18] | ||||||||
End point description | AUC0-tlast based on VWF:CB activity at initial PK assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Maximum Plasma Concentration (Cmax) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity [19] | ||||||||
End point description | Cmax based on VWF:Rco at initial PK assessment was reported. Unit of measure: International Units per deciliter (IU/dL). PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Maximum Plasma Concentration (Cmax) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity [20] | ||||||||
End point description | Cmax based on VWF:Ag activity at initial PK assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Maximum Plasma Concentration (Cmax) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity [21] | ||||||||
End point description | Cmax based on VWF:CB activity at initial PK assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Minimum Time to Reach the Maximum Plasma Concentration (Tmax) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity [22] | ||||||||
End point description | Tmax based on VWF:Rco activity at initial PK assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Minimum Time to Reach the Maximum Concentration (Tmax) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity [23] | ||||||||
End point description | Tmax based on VWF:Ag activity at initial PK assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Minimum Time to Reach the Maximum Plasma Concentration (Tmax) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity [24] | ||||||||
End point description | Tmax based on VWF:CB activity at initial PK assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Volume of Distribution at Steady State (Vss) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity [25] | ||||||||
End point description | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss based on VWF:Rco activity at initial assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Volume of Distribution at Steady State (Vss) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity [26] | ||||||||
End point description | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss based on VWF:Ag activity at initial assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Volume of Distribution at Steady State (Vss) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity [27] | ||||||||
End point description | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss based on VWF:CB activity at initial assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Clearance (CL) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity [28] | ||||||||
End point description | Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL based on VWF:Rco activity at initial PK assessment was reported. Unit of measure: deciliter per kilogram per hour (dL/kg/h). PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Clearance (CL) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity [29] | ||||||||
End point description | Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL based on VWF:Ag activity at initial PK assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analyzed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacokinetic Assessment: Clearance (CL) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity [30] | ||||||||
End point description | Clearance is defined as a quantitative measure of the rate at which a drug substance is removed from the body. CL based on VWF:CB activity at initial PK assessment was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analyzed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacodynamic (PD) Assessment: Maximum Plasma Concentration (Cmax) Based on Factor VIII Clotting (FVIII:C) Activity [31] | ||||||||
End point description | Cmax based on FVIII:C activity at initial PD assessment by the 1-stage clotting assay was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacodynamic Assessment: Minimum Time to Reach the Maximum Plasma Concentration (Tmax) Based on Factor VIII Clotting (FVIII:C) Activity [32] | ||||||||
End point description | Tmax based on FVIII:C activity at initial PD assessment by the 1-stage clotting assay was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||
End point title | Pharmacodynamic Assessment: Area Under the Plasma Concentration Versus Time Curve From Time 0 to the Last Measurable Concentration (AUC0-tlast) Based on Factor VIII Clotting (FVIII:C) Activity [33] | ||||||||
End point description | AUC0-tlast based on FVIII:C activity at initial PD assessment by the 1-stage clotting assay was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analyzed” were subjects who were evaluable for this end point. As planned, this end point was assessed only for prior on-demand subjects. | ||||||||
End point type | Secondary | ||||||||
End point timeframe | At baseline: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||
| Notes [33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Only descriptive data was planned to be analyzed for this endpoint. | |||||||||
| |||||||||
| No statistical analyses for this end point | |||||||||
| |||||||||||||
End point title | Pharmacokinetic Assessment at Steady State: Area Under the Plasma Concentration Versus Time Curve From Time 0 to end of the Partial Dosing Interval (AUC0- tau;ss) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity | ||||||||||||
End point description | AUC0-tau;ss based on VWF:Rco activity at steady state during end of study (Month 12) was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analyzed” were subjects who were evaluable for this end point. | ||||||||||||
End point type | Secondary | ||||||||||||
End point timeframe | At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||||||
| |||||||||||||
| No statistical analyses for this end point | |||||||||||||
| |||||||||||||
End point title | Pharmacokinetic Assessment at Steady State: Area Under the Plasma Concentration Versus Time Curve From Time 0 to end of the Partial Dosing Interval (AUC0- tau;ss) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity | ||||||||||||
End point description | AUC0-tau;ss based on VWF:Ag activity at steady state during end of study (Month 12) was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analyzed” were subjects who were evaluable for this end point. | ||||||||||||
End point type | Secondary | ||||||||||||
End point timeframe | At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||||||
| |||||||||||||
| No statistical analyses for this end point | |||||||||||||
| |||||||||||||
End point title | Pharmacokinetic Assessment at Steady State: Area Under the Plasma Concentration Versus Time Curve From Time 0 to end of the Partial Dosing Interval (AUC0- tau;ss) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity | ||||||||||||
End point description | AUC0-tau;ss based on VWF:CB activity at steady state during end of study (Month 12) was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analyzed” were subjects who were evaluable for this end point. | ||||||||||||
End point type | Secondary | ||||||||||||
End point timeframe | At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||||||
| |||||||||||||
| No statistical analyses for this end point | |||||||||||||
| |||||||||||||
End point title | Pharmacokinetics Assessment at Steady State: Maximum Plasma Concentration During the Partial Dosing Interval at Steady State (Cmax;ss) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity | ||||||||||||
End point description | Cmax;ss based on VWF:Rco activity at steady state during end of study (Month 12) was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. | ||||||||||||
End point type | Secondary | ||||||||||||
End point timeframe | At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||||||
| |||||||||||||
| No statistical analyses for this end point | |||||||||||||
| |||||||||||||
End point title | Pharmacokinetics Assessment at Steady State: Maximum Plasma Concentration During the Partial Dosing Interval at Steady State (Cmax;ss) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity | ||||||||||||
End point description | Cmax;ss based on VWF:Ag activity at steady state during end of study (Month 12) was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. | ||||||||||||
End point type | Secondary | ||||||||||||
End point timeframe | At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||||||
| |||||||||||||
| No statistical analyses for this end point | |||||||||||||
| |||||||||||||
End point title | Pharmacokinetics Assessment at Steady State: Maximum Plasma Concentration During the Partial Dosing Interval at Steady State (Cmax;ss) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity | ||||||||||||
End point description | Cmax;ss based on VWF:CB activity at steady state during end of study (Month 12) was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. | ||||||||||||
End point type | Secondary | ||||||||||||
End point timeframe | At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||||||
| |||||||||||||
| No statistical analyses for this end point | |||||||||||||
| |||||||||||||
End point title | Pharmacokinetics Assessment at Steady State: Minimum Time to Reach the Maximum Plasma Concentration at Steady State (Tmax;ss) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity | ||||||||||||
End point description | Tmax;ss based on VWF:Rco activity at steady state during end of study (Month 12) was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. | ||||||||||||
End point type | Secondary | ||||||||||||
End point timeframe | At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||||||
| |||||||||||||
| No statistical analyses for this end point | |||||||||||||
| |||||||||||||
End point title | Pharmacokinetics Assessment at Steady State: Minimum Time to Reach the Maximum Plasma Concentration at Steady State (Tmax;ss) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity | ||||||||||||
End point description | Tmax;ss based on VWF:Ag activity at steady state during end of study (Month 12) was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. | ||||||||||||
End point type | Secondary | ||||||||||||
End point timeframe | At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||||||
| |||||||||||||
| No statistical analyses for this end point | |||||||||||||
| |||||||||||||
End point title | Pharmacokinetics Assessment at Steady State: Minimum Time to Reach the Maximum Plasma Concentration at Steady State (Tmax;ss) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity | ||||||||||||
End point description | Tmax;ss based on VWF:CB activity at steady state during end of study (Month 12) was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. | ||||||||||||
End point type | Secondary | ||||||||||||
End point timeframe | At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||||||
| |||||||||||||
| No statistical analyses for this end point | |||||||||||||
| |||||||||||||
End point title | Pharmacokinetics Assessment at Steady State: Minimum Plasma Concentration During the Partial Dosing Interval at Steady State (Cmin;ss) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity | ||||||||||||
End point description | Cmin;ss based on VWF:Rco activity at steady state during end of study (Month 12) was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. Here "99999" refers to data not available and added as space-fillers as value was below the limit of quantification. | ||||||||||||
End point type | Secondary | ||||||||||||
End point timeframe | At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||||||
| |||||||||||||
| No statistical analyses for this end point | |||||||||||||
| |||||||||||||
End point title | Pharmacokinetics Assessment at Steady State: Minimum Plasma Concentration During the Partial Dosing Interval at Steady State (Cmin;ss) Based on Von Willebrand Factor Antigen (VWF:Ag) Activity | ||||||||||||
End point description | Cmin;ss based on VWF:Rco activity at steady state during end of study (Month 12) was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. | ||||||||||||
End point type | Secondary | ||||||||||||
End point timeframe | At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||||||
| |||||||||||||
| No statistical analyses for this end point | |||||||||||||
| |||||||||||||
End point title | Pharmacokinetics Assessment at Steady State: Minimum Plasma Concentration During the Partial Dosing Interval at Steady State (Cmin;ss) Based on Von Willebrand Factor Collagen Binding (VWF:CB) Activity | ||||||||||||
End point description | Cmin;ss based on VWF:CB activity at steady state during end of study (Month 12) was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. | ||||||||||||
End point type | Secondary | ||||||||||||
End point timeframe | At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||||||
| |||||||||||||
| No statistical analyses for this end point | |||||||||||||
| |||||||||||||
End point title | Pharmacodynamic Assessment at Steady State: Area Under the Plasma Concentration Versus Time Curve From Time 0 to end of the Partial Dosing Interval (AUC0- tau;ss) Based on Factor VIII Clotting (FVIII:C) Activity | ||||||||||||
End point description | AUC0-tau;ss based on FVIII:C activity at steady state during end of study (Month 12) was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analyzed” were subjects who were evaluable for this end point. | ||||||||||||
End point type | Secondary | ||||||||||||
End point timeframe | At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||||||
| |||||||||||||
| No statistical analyses for this end point | |||||||||||||
| |||||||||||||
End point title | Pharmacodynamic Assessment at Steady State: Maximum Plasma Concentration During the Partial Dosing Interval at Steady State (Cmax;ss) Based on Factor VIII Clotting (FVIII:C) Activity | ||||||||||||
End point description | Cmax;ss based on FVIII:C activity was assessed at steady state during end of study (Month 12) was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. | ||||||||||||
End point type | Secondary | ||||||||||||
End point timeframe | At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||||||
| |||||||||||||
| No statistical analyses for this end point | |||||||||||||
| |||||||||||||
End point title | Pharmacodynamic Assessment at Steady State: Minimum Time to Reach the Maximum Plasma Concentration at Steady State (Tmax;ss) Based on Factor VIII Clotting (FVIII:C) Activity | ||||||||||||
End point description | Tmax;ss based on FVIII:C activity at steady state during end of study (Month 12) was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. | ||||||||||||
End point type | Secondary | ||||||||||||
End point timeframe | At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||||||
| |||||||||||||
| No statistical analyses for this end point | |||||||||||||
| |||||||||||||
End point title | Pharmacodynamic Assessment at Steady State: Minimum Plasma Concentration During the Partial Dosing Interval at Steady State (Cmin;ss) Based on Factor VIII Clotting (FVIII:C) Activity | ||||||||||||
End point description | Cmin;ss based on FVIII:C activity at steady state during end of study (Month 12) was reported. PKFAS composed of all subjects who received at least one IP infusion and who provided at least one quantifiable pharmacokinetic or pharmacodynamic post dose measurement for pharmacokinetic and/or pharmacodynamics analysis. Here “number of subjects analysed” were subjects who were evaluable for this end point. | ||||||||||||
End point type | Secondary | ||||||||||||
End point timeframe | At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||||||
| |||||||||||||
| No statistical analyses for this end point | |||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||
End point title | Factor VIII (FVIII) Clotting Activity | ||||||||||||||||||||||||||||||||||||||||||||||||
End point description | FVIII clotting activity (FVIII:C) levels was assessed and reported as per pre-specified PK time points at Month 12. FAS will be composed of all participants who receive prophylactic IP treatment. Here “number of subjects analysed” were subjects who were evaluable for this end point. | ||||||||||||||||||||||||||||||||||||||||||||||||
End point type | Secondary | ||||||||||||||||||||||||||||||||||||||||||||||||
End point timeframe | At Month 12: Within 30 minutes pre-infusion; and post-infusion at 15, 30 minutes and 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours | ||||||||||||||||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||||||||||||||||||||||||||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Adverse events information | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events | From first dose of study drug up to end of study (approximately 32 months) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type | Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Dictionary used for adverse event reporting | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name | MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version | 23.0 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Reporting groups | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title | Switch Subjects | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description | Subjects who had taken prophylactic treatment with pdVWF prior to current study and switched to rVWF (vonicog alpha); received rVWF at an initial prophylactic dose of +/- 10 % of weekly pdVWF dose received prior to this study. Dose escalation to higher dose (up to 80 IU/kg per infusion) or frequency (up to 3 times a week or once a week depending on the total weekly dose and the dosing regimen used in their previous pdVWF prophylaxis regimen) was based on medical indication and investigator judgment. During this prophylaxis treatment period, any bleeding episodes requiring replacement therapy with VWF concentrate was treated with rVWF with or without rFVIII (ADVATE); the dose was determined according to the bleeding type and severity, and was adjusted based on the subject’s clinical response. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title | On-Demand Subjects | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description | Subjects who had taken only on-demand VWF prior to the current study received rVWF (vonicog alpha) initial prophylactic treatment at a dose range of 50 +/- 10 IU/kg, intravenous infusion, twice per week for up to 12 months. Dose was escalated up to 80 IU/kg infusion, dosing frequency up to 3 times a week based on medical indication and investigator judgement. During this prophylaxis treatment period, any bleeding episodes requiring substitution therapy with VWF concentrate was treated with rVWF with or without rFVIII (ADVATE); the dose was determined according to the bleeding type and severity, and was adjusted based on the subject's clinical response. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) | |||
| Were there any global substantial amendments to the protocol? Yes | |||
Date | Amendment | ||
03 Aug 2017 | Protocol Amendment 3: To define the threshold considered as relevant ABR reduction relative to subjects’ historical ABR. Include 15 minutes, 3 hours and 30 hours PK sampling timepoints. To clearly define the ADVATE use. | ||
12 Mar 2018 | Protocol Amendment 6: Updated study design. Provided further clarifications on SAE reporting. Added definition of severe VWD. Defined the new study timeline. Provided further clarifications to the purpose of the study. pdVWF switch subject, a new study cohort added in the study. Updated the eligibility of switch subjects and added study design, dosing guide, sample collection and new outcome measures for the switch cohort. | ||
Interruptions (globally) | |||
| Were there any global interruptions to the trial? No | |||
Limitations and caveats | |||
| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||