rVWF IN PROPHYLAXIS

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).

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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]).

IR based on VWF:Ag activity at initial PK assessment was reported.

IR at the maximum plasma concentration of VWF:CB activity at initial PK assessment was reported.

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.

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.

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.

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.

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.

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.

AUC0-∞ based on VWF:Rco activity at initial PK assessment was reported. Unit of measure: International Units*hour per deciliter (IU*h/dL).

AUC0-∞ based on VWF:Ag activity at initial PK assessment was reported.

AUC0-∞ based on VWF:CB activity at initial PK assessment was reported.

AUC0-tlast based on VWF:Rco activity at initial PK assessment was reported.

AUC0-tlast based on VWF:Ag activity at initial PK assessment was reported.

AUC0-tlast based on VWF:CB activity at initial PK assessment was reported.

Cmax based on VWF:Rco at initial PK assessment was reported. Unit of measure: International Units per deciliter (IU/dL).

Cmax based on VWF:Ag activity at initial PK assessment was reported.

Cmax based on VWF:CB activity at initial PK assessment was reported.

Tmax based on VWF:Rco activity at initial PK assessment was reported.

Tmax based on VWF:Ag activity at initial PK assessment was reported.

Tmax based on VWF:CB activity at initial PK assessment was reported.

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.

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.

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.

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).

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.

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.

Cmax based on FVIII:C activity at initial PD assessment by the 1-stage clotting assay was reported.

Tmax based on FVIII:C activity at initial PD assessment by the 1-stage clotting assay was reported.

AUC0-tlast based on FVIII:C activity at initial PD assessment by the 1-stage clotting assay was reported.

AUC0-tau;ss based on VWF:Rco activity at steady state during end of study (Month 12) was reported.

AUC0-tau;ss based on VWF:Ag activity at steady state during end of study (Month 12) was reported.

AUC0-tau;ss based on VWF:CB activity at steady state during end of study (Month 12) was reported.

Cmax;ss based on VWF:Rco activity at steady state during end of study (Month 12) was reported.

Cmax;ss based on VWF:Ag activity at steady state during end of study (Month 12) was reported.

Cmax;ss based on VWF:CB activity at steady state during end of study (Month 12) was reported.

Tmax;ss based on VWF:Rco activity at steady state during end of study (Month 12) was reported.

Tmax;ss based on VWF:Ag activity at steady state during end of study (Month 12) was reported.

Tmax;ss based on VWF:CB activity at steady state during end of study (Month 12) was reported.

Cmin;ss based on VWF:Rco activity at steady state during end of study (Month 12) was reported.

Cmin;ss based on VWF:Rco activity at steady state during end of study (Month 12) was reported.

Cmin;ss based on VWF:CB activity at steady state during end of study (Month 12) was reported.

AUC0-tau;ss based on FVIII:C activity at steady state during end of study (Month 12) was reported.

Cmax;ss based on FVIII:C activity was assessed at steady state during end of study (Month 12) was reported.

Tmax;ss based on FVIII:C activity at steady state during end of study (Month 12) was reported.

Cmin;ss based on FVIII:C activity at steady state during end of study (Month 12) was reported.

FVIII clotting activity (FVIII:C) levels was assessed and reported as per pre-specified PK time points at Month 12.