A Study of Recombinant Von Willebrand Factor (rVWF) With or Without ADVATE in Children With Severe Von Willebrand Disease (VWD)

Study Overview
=================
Brief Summary
-----------------
The main aim of the study is to check effectiveness, side effects, and tolerability of recombinant von Willebrand Factor (rVWF), with or without ADVATE, in the treatment and control of nonsurgical bleeding events in pediatric participants (less than (<)18 years of age) with severe hereditary von Willebrand disease (VWD). The participants will be treated with rVWF for 12-18 months. Their von Willebrand Disease will be treated by their doctor according to their doctor's usual clinical practice. During the study, participants will be followed up at clinics or over telephone calls.

Official Title
-----------------
A Phase 3, Prospective, Multicenter, Uncontrolled, Open-Label Clinical Study to Determine the Efficacy, Safety, and Tolerability of rVWF With or Without ADVATE in the Treatment and Control of Bleeding Episodes, the Efficacy and Safety of rVWF in Elective and Emergency Surgeries, and the Pharmacokinetics (PK) of rVWF in Children Diagnosed With Severe Von Willebrand Disease

Conditions
-----------------
Von Willebrand Disease

Intervention / Treatment
-----------------
* Biological: von Willebrand factor (Recombinant)
* Biological: Antihemophilic Factor (Recombinant)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of severe von Willebrand disease (VWD) (defined as von Willebrand factor: ristocetin cofactor [VWF:RCo] less than [<] 20 percent [%]): Type 1 (VWF:RCo <20 International Units per deciliter [IU/dL]); or Type 2A (VWF:RCo <20 IU/dL), Type 2B (as diagnosed by genotype), Type 2N (Factor VIII coagulation activity [FVIII:C] <10 % and historically documented genetics), Type 2M; or Type 3 (VWF:Ag less than or equal to [=<] 3 IU/dL). Age 0 to <18 years at the time of Screening. The participant has provided assent (if appropriate) and legally authorized representative(s) has provided informed consent. If female of childbearing potential, participant presents with a negative serum pregnancy test. If applicable, participant agrees to employ adequate birth control measures for the duration of the study. The participant and/or the legally authorized representative are willing and able to comply with the requirements of the protocol, which should also be confirmed based on a pre-screening evaluation held between the Investigator and the Sponsor, to ensure no eminent risk is present that could challenge the participants compliance with the study requirements. Additional inclusion criteria for both previously treated participants and participants undergoing surgery are as follows: Unable to tolerate or are inadequately responsive to deamino-delta-D-arginine vasopressin (DDAVP). The participant has had a minimum of 1 documented bleed requiring VWF coagulation factor replacement therapy (i.e. treatment with a VWF product) during the previous 12 months prior to enrollment and overall historically 3 or more exposure days (EDs) to VWF replacement therapy. Additional inclusion criterion for previously untreated participants are as follows: - The participant has not received prior VWF coagulation factor replacement therapy. Exclusion Criteria: Diagnosis of pseudo-VWD or another hereditary or acquired coagulation disorder (eg, qualitative and quantitative platelet disorders or elevated prothrombin time [PT]/international normalized ratio [INR] greater than [>] 1.4). History or presence of a VWF inhibitor at Screening. History or presence of a Factor VIII (FVIII) inhibitor with a titer greater than or equal [>=] 0.4 Bethesda units (BU) (by Nijmegen assay) or >=0.6 BU (by Bethesda assay). Documented history of a VWF: RCo half-life <6 hours. Known hypersensitivity to any of the components of the study drug, such as mouse or hamster proteins. Medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis/asthma, food allergies, or animal allergies. Medical history of a thromboembolic event. Human immunodeficiency virus (HIV) positive, with an absolute CD4 count <200/ cubic millimeter (mm^3). In the judgment of the Investigator, the participant has another clinically significant concomitant disease (e.g. uncontrolled hypertension, cancer) that may pose additional risks for the participant. Diagnosis of significant liver disease, as evidenced by, but not limited to, any of the following: serum alanine aminotransferase (ALT) of 5 times the upper limit of normal; hypoalbuminemia; portal vein hypertension (e.g. presence of otherwise unexplained splenomegaly, history of esophageal varices) or liver cirrhosis classified as Child B or C. Diagnosis of renal disease, with a serum creatinine level >=2.5 milligram per deciliter (mg/dL). Immunomodulatory drug treatment other than anti-retroviral chemotherapy (e.g. α-interferon, or corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 milligram per day [mg/day] (excluding topical treatment [e.g. ointments, nasal sprays]), within 30 days prior to signing the informed consent (or assent, if appropriate). If female, participant is pregnant or lactating at the time informed consent (or assent, if appropriate) is obtained. Participant has participated in another clinical study involving an investigational product (IP), other than rVWF with or without ADVATE, or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP other than rVWF or investigational device during the course of this study. Participant's legal representative is a family member or employee of the Investigator.

Ages Eligible for Study
-----------------
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: On-demand Treatment<br>Participants will receive recombinant von Willebrand factor (rVWF) treatment for non-surgical bleeding episodes over a 12 to 18-month period. | Biological: von Willebrand factor (Recombinant)<br>* Lyophilized powder and solvent to prepare solution for injection.<br>* Other names: BAX 111;Biological: Antihemophilic Factor (Recombinant)<br>* Packaged in single boxes with 2 glass vials, with one vial containing the lyophilized ADVATE and the second vial containing the diluent.<br>* Other names: rFVIII;|
| Experimental: Elective Surgery<br>12-24 hours prior to surgery and within 3 hours of surgery. Minor surgery: infuse every 12-24 hours for at least 48 hours based on post-operative dosing. Oral Surgery: infuse at least once within first 8-12 hours post-surgery based on post-operative dosing. Major Surgery: infuse every 12-24 hours for at least first 96 hours post-surgery based on post-operative dosing. | Biological: von Willebrand factor (Recombinant)<br>* Lyophilized powder and solvent to prepare solution for injection.<br>* Other names: BAX 111;Biological: Antihemophilic Factor (Recombinant)<br>* Packaged in single boxes with 2 glass vials, with one vial containing the lyophilized ADVATE and the second vial containing the diluent.<br>* Other names: rFVIII;|
| Experimental: Emergency Surgery<br>Within 3 hours prior to surgery. Minor surgery: infuse every 12-24 hours for at least 48 hours based on post-operative dosing. Oral Surgery: infuse at least once within first 8-12 hours post-surgery based on post-operative dosing. Major Surgery: infuse every 12-24 hours for at least first 96 hours post-surgery based on post-operative dosing. | Biological: von Willebrand factor (Recombinant)<br>* Lyophilized powder and solvent to prepare solution for injection.<br>* Other names: BAX 111;Biological: Antihemophilic Factor (Recombinant)<br>* Packaged in single boxes with 2 glass vials, with one vial containing the lyophilized ADVATE and the second vial containing the diluent.<br>* Other names: rFVIII;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hemostatic Efficacy | Treatment success for rVWF-treated nonsurgical bleeding episodes (using a 4-point scale: Excellent, Good, Moderate, None). | Within 24 hours after the last infusion of study drug following the onset of the bleeding episode (if/when the severity and/or duration of the bleeding requires the infusion of the study drug) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Treated Nonsurgical Bleeding Episodes With an Efficacy Rating of 'Excellent' or 'Good' | If/when the severity and/or duration of the bleeding requires the infusion of the study drug. | Throughout the study duration of approximately 6.5 years | 
| Number of Infusions per Bleeding Episode |  | Throughout the study duration of approximately 6.5 years | 
| Number of Recombinant Von Willebrand Factor (rVWF) Units per Bleeding Episode |  | Throughout the study duration of approximately 6.5 years | 
| Number of ADVATE Units (if needed) per Bleeding Episode |  | Throughout the study duration of approximately 6.5 years | 
| Elective or Emergency Surgery: Assessment of Hemostatic Efficacy - Immediately After Surgery | Assessed by the operating surgeon, based on a 4-point ordinal scale: Excellent, Good, Moderate, None. | Immediately after surgery | 
| Elective or Emergency Surgery: Overall Assessment of Hemostatic Efficacy 24 Hours After the Last Perioperative Infusion of rVWF | Assessed by the Investigator (hematologist) on a 4-point ordinal scale: Excellent, Good, Moderate, None. | 24 hours after last perioperative rVWF infusion | 
| Elective or Emergency surgery: Overall Assessment of Hemostatic Efficacy Day 7 Post-operative | Assessed by the Investigator (hematologist) on a 4-point ordinal scale: Excellent, Good, Moderate, None. | Post-operative Day 7 | 
| Elective or Emergency surgery: Overall Assessment of Hemostatic Efficacy Day 14 Post-operative | Assessed by the Investigator (hematologist) on a 4-point ordinal scale: Excellent, Good, Moderate, None. | Post-operative Day 14 | 
| Incidence and Severity of Adverse Events (AEs) |  | Throughout the study period of approximately 6.5 years | 
| Incidence of Thrombotic Events |  | Throughout the study period of approximately 6.5 years | 
| Incidence of Severe Hypersensitivity Reactions |  | Throughout the study period of approximately 6.5 years | 
| Development of Neutralizing Antibodies to von Willebrand Factor (VWF) and Factor VIII (FVIII) |  | Throughout the study period of approximately 6.5 years | 
| Development of Total Binding Antibodies to von Willebrand Factor (VWF) |  | Throughout the study period of approximately 6.5 years | 
| Development of Antibodies to Chinese Hamster Ovary (CHO) Proteins, Murine Immunoglobulin G (IgG), and rFurin |  | Throughout the study period of approximately 6.5 years | 
| Area Under the Plasma Concentration/Time Curve From 0 to 96 Hours Post-Infusion (AUC0-96h) for Von Willebrand factor: ristocetin cofactor (VWF:Rco), von Willebrand factor: antigen (VWF:Ag) and von Willebrand factor: collagen binding capacity (VWF:CB) |  | Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours | 
| Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-inf) for VWF:RCo, VWF:Ag and VWF:CB |  | Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours | 
| Mean Residence Time (MRT) for VWF:RCo, VWF:Ag and VWF:CB |  | Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours | 
| Time to Reach Maximal Plasma Concentration (Tmax) for VWF:RCo, VWF:Ag and VWF:CB |  | Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours | 
| Maximal Plasma Concentration (Cmax) for VWF:RCo, VWF:Ag and VWF:CB |  | Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours | 
| Clearance (CL) for VWF:RCo, VWF:Ag and VWF:CB |  | Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours | 
| Incremental Recovery (IR) for VWF:RCo, VWF:Ag and VWF:CB |  | Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours | 
| In-vivo Recovery (IVR) for VWF:RCo, VWF:Ag and VWF:CB |  | Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours | 
| Elimination Phase Half-life (T1/2) for VWF:RCo, VWF:Ag and VWF:CB |  | Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours | 
| Volume of Distribution at Steady State (Vss) for VWF:RCo, VWF:Ag and VWF:CB |  | Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours | 
| Area Under the Plasma Concentration/Time Curve From 0 to 96 Hours Post-infusion (AUC0-96h) for Factor VIII (FVIII) Activity |  | Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours |