Trial Outcomes & Findings for rVWF IN PROPHYLAXIS (NCT NCT02973087)

Results Overview

ABR for treated spontaneous BEs while on prophylactic treatment with rVWF through month 12 of treatment period/observation period (in years), where an observation period = (date of completion/termination - date of first dose + 1)/365.2425. Bleeds occurred at the same anatomical location with the same etiology within 24 hours after onset of the first bleed were considered a single bleed. Bleeding occurred at multiple locations related to the same injury were considered as a single bleeding episode. Historical observation period for historical BEs was 365 days prior to first dose of study drug. On-study observation period started on the day of 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 bleeding episodes (not related to trauma) during prophylactic treatment with rVWF was reported as a ratio of mean ABRs (on-study ABR:historical ABR).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

29 participants

Primary outcome timeframe

Up to 12 months

Results posted on

2021-08-06

Participant Flow

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 participant first visit) and 06 July 2020 (last participant last visit).

A total of 29 participants were screened, out of which 6 participants were screen failures and 23 participants 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).

Participant milestones

Participant milestones
Measure	Prior On-demand Participants Participants 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 participant's clinical response.	Switch Participants Participants 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 participant's clinical response.
Overall Study STARTED	13	10
Overall Study COMPLETED	9	8
Overall Study NOT COMPLETED	4	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Prior On-demand Participants Participants 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 participant's clinical response.	Switch Participants Participants 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 participant's clinical response.
Overall Study Withdrawal by Subject	2	1
Overall Study Adverse Event	1	0
Overall Study other	1	1

Baseline Characteristics

rVWF IN PROPHYLAXIS

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Prior On-demand Participants n=13 Participants Participants 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 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 (rFVIII); the dose was determined according to the bleeding type and severity, and was adjusted based on the participant's clinical response.	Switch Participants n=10 Participants Participants who had taken prophylactic treatment with 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 participant's clinical response.	Total n=23 Participants Total of all reporting groups
Age, Continuous	38.0 years STANDARD_DEVIATION 17.6 • n=93 Participants	43.9 years STANDARD_DEVIATION 21.8 • n=4 Participants	40.6 years STANDARD_DEVIATION 19.3 • n=27 Participants
Sex: Female, Male Female	8 Participants n=93 Participants	3 Participants n=4 Participants	11 Participants n=27 Participants
Sex: Female, Male Male	5 Participants n=93 Participants	7 Participants n=4 Participants	12 Participants n=27 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=93 Participants	2 Participants n=4 Participants	2 Participants n=27 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	13 Participants n=93 Participants	7 Participants n=4 Participants	20 Participants n=27 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	1 Participants n=4 Participants	1 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Asian	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Black or African American	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) White	13 Participants n=93 Participants	9 Participants n=4 Participants	22 Participants n=27 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	1 Participants n=4 Participants	1 Participants n=27 Participants

PRIMARY outcome

Timeframe: Up to 12 months

Population: Full analysis set (FAS) composed of all participants who received prophylactic IP treatment.

ABR for treated spontaneous BEs while on prophylactic treatment with rVWF through month 12 of treatment period/observation period (in years), where an observation period = (date of completion/termination - date of first dose + 1)/365.2425. Bleeds occurred at the same anatomical location with the same etiology within 24 hours after onset of the first bleed were considered a single bleed. Bleeding occurred at multiple locations related to the same injury were considered as a single bleeding episode. Historical observation period for historical BEs was 365 days prior to first dose of study drug. On-study observation period started on the day of 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 bleeding episodes (not related to trauma) during prophylactic treatment with rVWF was reported as a ratio of mean ABRs (on-study ABR:historical ABR).

Outcome measures

Outcome measures
Measure	Prior On-demand Participants n=13 Participants Participants 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 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 (rFVIII); the dose was determined according to the bleeding type and severity, and was adjusted based on the participant's clinical response.	Switch Participants n=10 Participants Participants who had taken prophylactic treatment with 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 participant's clinical response.
Ratio of Annualized Bleeding Rate (ABR) for Spontaneous Bleeding Episodes (BEs) (On-study ABR / Historical ABR) Assessed by Investigator During Prophylactic Treatment With rVWF Through Month 12	0.085 ratio Interval 0.021 to 0.346	0.550 ratio Interval 0.086 to 3.523

SECONDARY outcome

Timeframe: Up to 12 months

Population: FAS composed of all participants who received prophylactic IP treatment. This outcome measure was analyzed only for prior on-demand participants treated for spontaneous BEs.

For prior on-demand participants, 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) prophylaxis relative to the participant's own historical treated spontaneous ABR. Percentage of participants with ABR percent reduction success for on-demand cohort was reported.

Outcome measures

Outcome measures
Measure	Prior On-demand Participants n=13 Participants Participants 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 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 (rFVIII); the dose was determined according to the bleeding type and severity, and was adjusted based on the participant's clinical response.	Switch Participants Participants who had taken prophylactic treatment with 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 participant's clinical response.
Percentage of Prior On-demand Participants Achieved Spontaneous ABR Percent Reduction Success Through Month 12	92.3 percentage of participants Interval 64.0 to 99.8	—

SECONDARY outcome

Timeframe: Up to 12 months

Population: FAS composed of all participants who received prophylactic IP treatment. This outcome measure was analyzed only for switch participants treated for spontaneous BEs.

For switch participants, spontaneous ABR preservation success was defined as achieving an ABR for treated spontaneous BEs during first 12 months of rVWF (vonicog alfa) prophylaxis that was no greater than the participant's own historical ABR for treated spontaneous BEs during prophylactic treatment with pdVWF. Percentage of participants with ABR preservation success in switch cohort was reported.

Outcome measures

Outcome measures
Measure	Prior On-demand Participants n=10 Participants Participants 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 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 (rFVIII); the dose was determined according to the bleeding type and severity, and was adjusted based on the participant's clinical response.	Switch Participants Participants who had taken prophylactic treatment with 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 participant's clinical response.
Percentage of Switch Participants With Spontaneous ABR Preservation Success Through Month 12	90.0 percentage of participants Interval 55.5 to 99.7	—

SECONDARY outcome

Timeframe: Baseline through Month 12

Population: FAS composed of all participants who received prophylactic IP treatment.

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.

Outcome measures

Outcome measures
Measure	Prior On-demand Participants n=13 Participants Participants 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 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 (rFVIII); the dose was determined according to the bleeding type and severity, and was adjusted based on the participant's clinical response.	Switch Participants n=10 Participants Participants who had taken prophylactic treatment with 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 participant's clinical response.
Number of Participants Based on Categorized Spontaneous ABR (sABR) Through Month 12 Historical · 0 BEs	0 Participants	6 Participants
Number of Participants Based on Categorized Spontaneous ABR (sABR) Through Month 12 Historical · >0 through 2 BEs	0 Participants	3 Participants
Number of Participants Based on Categorized Spontaneous ABR (sABR) Through Month 12 Historical · >2 through 5 BEs	10 Participants	0 Participants
Number of Participants Based on Categorized Spontaneous ABR (sABR) Through Month 12 Historical · >5 BEs	3 Participants	1 Participants
Number of Participants Based on Categorized Spontaneous ABR (sABR) Through Month 12 On-Study Through Month 12 · 0 BEs	11 Participants	7 Participants
Number of Participants Based on Categorized Spontaneous ABR (sABR) Through Month 12 On-Study Through Month 12 · >0 through 2 BEs	0 Participants	1 Participants
Number of Participants Based on Categorized Spontaneous ABR (sABR) Through Month 12 On-Study Through Month 12 · >2 through 5 BEs	1 Participants	1 Participants
Number of Participants Based on Categorized Spontaneous ABR (sABR) Through Month 12 On-Study Through Month 12 · >5 BEs	1 Participants	1 Participants

SECONDARY outcome

Timeframe: Up to 12 months

Population: FAS composed of all participants who received prophylactic IP treatment.

For each participant, 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 participant during prophylactic treatment With rVWF through 12 months was calculated.

Outcome measures

Outcome measures
Measure	Prior On-demand Participants n=13 Participants Participants 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 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 (rFVIII); the dose was determined according to the bleeding type and severity, and was adjusted based on the participant's clinical response.	Switch Participants n=10 Participants Participants who had taken prophylactic treatment with 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 participant's clinical response.
Total Number of Infusions Administered Per Participant During Prophylactic Treatment With rVWF Through Month 12	65.1 infusions Standard Deviation 38.4	87.8 infusions Standard Deviation 30.2

SECONDARY outcome

Timeframe: Up to 12 months

Population: FAS composed of all participants who received prophylactic IP treatment.

Average number of infusions per week per participant during prophylactic treatment With rVWF through 12 months was calculated.

Outcome measures

Outcome measures
Measure	Prior On-demand Participants n=13 Participants Participants 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 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 (rFVIII); the dose was determined according to the bleeding type and severity, and was adjusted based on the participant's clinical response.	Switch Participants n=10 Participants Participants who had taken prophylactic treatment with 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 participant's clinical response.
Average Number of Infusions Per Week Per Participant During Prophylactic Treatment With rVWF Through Month 12	1.88 infusions per week Standard Deviation 0.7	1.85 infusions per week Standard Deviation 0.4

SECONDARY outcome

Timeframe: Up to 12 months

Population: FAS composed of all participants who received prophylactic IP treatment.

For each participant, 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 participant during prophylactic treatment was reported.

Outcome measures

Outcome measures
Measure	Prior On-demand Participants n=13 Participants Participants 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 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 (rFVIII); the dose was determined according to the bleeding type and severity, and was adjusted based on the participant's clinical response.	Switch Participants n=10 Participants Participants who had taken prophylactic treatment with 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 participant's clinical response.
Total Weight Adjusted Consumption of rVWF Per Participant During Prophylactic Treatment Through Month 12	3431.584 IU/kg Standard Deviation 2117.6562	4433.752 IU/kg Standard Deviation 1844.8761

SECONDARY outcome

Timeframe: Up to 12 months

Population: FAS composed of all participants who received prophylactic IP treatment.

Number 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.

Outcome measures

Outcome measures
Measure	Prior On-demand Participants n=13 Participants Participants 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 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 (rFVIII); the dose was determined according to the bleeding type and severity, and was adjusted based on the participant's clinical response.	Switch Participants n=10 Participants Participants who had taken prophylactic treatment with 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 participant's clinical response.
Number of Treated Spontaneous BEs by Location of Bleeding While on Prophylactic Treatment With rVWF Through Month 12 Oral and other mucosa	5 number of BEs	14 number of BEs
Number of Treated Spontaneous BEs by Location of Bleeding While on Prophylactic Treatment With rVWF Through Month 12 Menorrhagia	3 number of BEs	0 number of BEs
Number of Treated Spontaneous BEs by Location of Bleeding While on Prophylactic Treatment With rVWF Through Month 12 Hemarthrosis	0 number of BEs	1 number of BEs
Number of Treated Spontaneous BEs by Location of Bleeding While on Prophylactic Treatment With rVWF Through Month 12 Other	1 number of BEs	0 number of BEs
Number of Treated Spontaneous BEs by Location of Bleeding While on Prophylactic Treatment With rVWF Through Month 12 Unknown	0 number of BEs	3 number of BEs

SECONDARY outcome

Timeframe: From first dose of study drug up to end of study (approximately 32 months)

Population: SAS composed of all participants who received any amount of IP (rVWF, vonicog alpha).

An adverse event (AE) is defined as any untoward medical occurrence in a participant 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 participants with TEAEs and serious TEAEs were reported.

Outcome measures

Outcome measures
Measure	Prior On-demand Participants n=13 Participants Participants 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 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 (rFVIII); the dose was determined according to the bleeding type and severity, and was adjusted based on the participant's clinical response.	Switch Participants n=10 Participants Participants who had taken prophylactic treatment with 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 participant's clinical response.
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs Participants With TEAEs	10 Participants	7 Participants
Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs Participants with serious TEAEs	1 Participants	2 Participants

SECONDARY outcome

Timeframe: From first dose of study drug up to end of study (approximately 32 months)

Population: SAS composed of all participants who received any amount of IP (rVWF, vonicog alpha).

An AE is defined as any untoward medical occurrence in a participant 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. Participants were counted by considering the maximum severity of TEAEs.

Outcome measures

Outcome measures
Measure	Prior On-demand Participants n=13 Participants Participants 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 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 (rFVIII); the dose was determined according to the bleeding type and severity, and was adjusted based on the participant's clinical response.	Switch Participants n=10 Participants Participants who had taken prophylactic treatment with 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 participant's clinical response.
Number of Participants Based on Severity of TEAEs Mild	7 Participants	4 Participants
Number of Participants Based on Severity of TEAEs Moderate	1 Participants	2 Participants
Number of Participants Based on Severity of TEAEs Severe	2 Participants	1 Participants

SECONDARY outcome

Timeframe: From first dose of study drug up to end of study (approximately 32 months)

Population: SAS composed of all participants who received any amount of IP (rVWF, vonicog alpha).

An AE was defined as any untoward medical occurrence in a participant 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 participants with TEAEs based causality was reported.

Outcome measures

Outcome measures
Measure	Prior On-demand Participants n=13 Participants Participants 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 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 (rFVIII); the dose was determined according to the bleeding type and severity, and was adjusted based on the participant's clinical response.	Switch Participants n=10 Participants Participants who had taken prophylactic treatment with 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 participant's clinical response.
Number of Participants With TEAEs Based Causality	1 Participants	0 Participants

SECONDARY outcome

Timeframe: From first dose of study drug up to end of study (approximately 32 months)

Population: SAS composed of all participants who received any amount of IP (rVWF, vonicog alpha).

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 participants with thromboembolic events as TEAEs of special interest was reported.

Outcome measures

Outcome measures
Measure	Prior On-demand Participants n=13 Participants Participants 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 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 (rFVIII); the dose was determined according to the bleeding type and severity, and was adjusted based on the participant's clinical response.	Switch Participants n=10 Participants Participants who had taken prophylactic treatment with 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 participant's clinical response.
Number of Participants With Thromboembolic Events	1 Participants	0 Participants

SECONDARY outcome

Timeframe: From first dose of study drug up to end of study (approximately 32 months)

Population: SAS composed of all participants who received any amount of IP (rVWF, vonicog alpha).

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 participants with hypersensitivity reactions as TEAEs of special interest was calculated.

Outcome measures

Outcome measures
Measure	Prior On-demand Participants n=13 Participants Participants 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 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 (rFVIII); the dose was determined according to the bleeding type and severity, and was adjusted based on the participant's clinical response.	Switch Participants n=10 Participants Participants who had taken prophylactic treatment with 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 participant's clinical response.
Number of Participants With Hypersensitivity Reactions	0 Participants	1 Participants

SECONDARY outcome

Timeframe: Baseline through Month 12

Population: SAS composed of all participants who received any amount of IP (rVWF, vonicog alpha).

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 participants who developed neutralizing antibodies to rVWF and FVIII were assessed.

Outcome measures

Outcome measures
Measure	Prior On-demand Participants n=13 Participants Participants 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 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 (rFVIII); the dose was determined according to the bleeding type and severity, and was adjusted based on the participant's clinical response.	Switch Participants n=10 Participants Participants who had taken prophylactic treatment with 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 participant's clinical response.
Number of Participants Who Developed Neutralizing Antibodies to Von Willebrand Factor (rVWF) and Factor VIII (FVIII)	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline through Month 12

Population: SAS composed of all participants who received any amount of IP (rVWF, vonicog alpha).

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 participants who developed of total binding antibodies to rVWF and FVIII was assessed.

Outcome measures

Outcome measures
Measure	Prior On-demand Participants n=13 Participants Participants 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 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 (rFVIII); the dose was determined according to the bleeding type and severity, and was adjusted based on the participant's clinical response.	Switch Participants n=10 Participants Participants who had taken prophylactic treatment with 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 participant's clinical response.
Number of Participants Who Developed of Total Binding Antibodies to Von Willebrand Factor (rVWF) and Factor VIII (FVIII)	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline through Month 12

Population: SAS composed of all participants who received any amount of IP (rVWF, vonicog alpha).

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 participants who developed binding antibodies to CHO proteins, Mouse IgG and/or rFurin was assessed.

Outcome measures

Outcome measures
Measure	Prior On-demand Participants n=13 Participants Participants 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 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 (rFVIII); the dose was determined according to the bleeding type and severity, and was adjusted based on the participant's clinical response.	Switch Participants n=10 Participants Participants who had taken prophylactic treatment with 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 participant's clinical response.
Number of Participants Who Developed Binding Antibodies to Chinese Hamster Ovary (CHO) Proteins, Mouse Immunoglobulin G (IgG) and/or rFurin	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline up to end of study (approximately 32 months)

Population: SAS composed of all participants who received any amount of IP (rVWF, vonicog alpha).

Vital signs included blood pressure (systolic and diastolic), pulse rate, respiratory rate and body temperature. Number of participants with clinically significant change from baseline in vital signs was assessed.

Outcome measures

Outcome measures
Measure	Prior On-demand Participants n=13 Participants Participants 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 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 (rFVIII); the dose was determined according to the bleeding type and severity, and was adjusted based on the participant's clinical response.	Switch Participants n=10 Participants Participants who had taken prophylactic treatment with 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 participant's clinical response.
Number of Participants With Clinically Significant Change From Baseline in Vital Signs	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline up to end of study (approximately 32 months)

Population: SAS composed of all participants who received any amount of IP (rVWF, vonicog alpha).

Clinical laboratory parameters included hematology and clinical chemistry assessments. Number of participants with clinically significant change from baseline in clinical laboratory parameters was assessed.