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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- 入组人数
- 47
- 试验地点
- 92
- 主要终点
- Hemostatic Efficacy
研究概览
简要总结
The main aim of the study is to check effectiveness, side effects, and tolerability of vonicog alfa (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 vonicog alfa 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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- — 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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 are inadequately responsive to, or not a good candidate for 1-deamino-8-D-arginine vasopressin (DDAVP). Examples of participants who are not good candidates for DDAVP include participants with type 2B or type 3 VWD.
- •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.
排除标准
- •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 vonicog alfa 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 vonicog alfa or investigational device during the course of this study.
- •Participant's legal representative is a family member or employee of the Investigator.
研究组 & 干预措施
On-demand Treatment
Participants will receive vonicog alfa (recombinant von Willebrand factor [rVWF]) treatment for non-surgical bleeding episodes over a 12 to 18-month period.
干预措施: Antihemophilic Factor (Recombinant) (Biological)
Elective Surgery
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.
干预措施: Antihemophilic Factor (Recombinant) (Biological)
On-demand Treatment
Participants will receive vonicog alfa (recombinant von Willebrand factor [rVWF]) treatment for non-surgical bleeding episodes over a 12 to 18-month period.
干预措施: Vonicog alfa (Biological)
Elective Surgery
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.
干预措施: Vonicog alfa (Biological)
Emergency Surgery
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.
干预措施: Vonicog alfa (Biological)
Emergency Surgery
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.
干预措施: Antihemophilic Factor (Recombinant) (Biological)
结局指标
主要结局
Hemostatic Efficacy
时间窗: 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)
Treatment success for vonicog alfa-treated nonsurgical bleeding episodes (using a 4-point scale: Excellent, Good, Moderate, None).
次要结局
- Number of Vonicog Alfa Units per Bleeding Episode(Throughout the study duration of approximately 8.5 years)
- Number of ADVATE Units (if needed) per Bleeding Episode(Throughout the study duration of approximately 8.5 years)
- Incidence of Thromboembolic Events(Throughout the study period of approximately 8.5 years)
- Incidence of Severe Hypersensitivity Reactions(Throughout the study period of approximately 8.5 years)
- Development of Neutralizing Antibodies to von Willebrand Factor (VWF) and Factor VIII (FVIII)(Throughout the study period of approximately 8.5 years)
- Development of Total Binding Antibodies to von Willebrand Factor (VWF)(Throughout the study period of approximately 8.5 years)
- Development of Antibodies to Chinese Hamster Ovary (CHO) Proteins, Murine Immunoglobulin G (IgG), and rFurin(Throughout the study period of approximately 8.5 years)
- Incidence and Severity of Adverse Events (AEs)(Throughout the study period of approximately 8.5 years)
- Number of Treated Nonsurgical Bleeding Episodes With an Efficacy Rating of 'Excellent' or 'Good'(Throughout the study duration of approximately 8.5 years)
- Number of Infusions per Bleeding Episode(Throughout the study duration of approximately 8.5 years)
- Elective or Emergency Surgery: Assessment of Hemostatic Efficacy - Immediately After Surgery(Immediately after surgery)
- Elective or Emergency Surgery: Overall Assessment of Hemostatic Efficacy 24 Hours After the Last Perioperative Infusion of rVWF(24 hours after last perioperative rVWF infusion)
- Elective or Emergency surgery: Overall Assessment of Hemostatic Efficacy Day 7 Post-operative(Post-operative Day 7)
- Elective or Emergency surgery: Overall Assessment of Hemostatic Efficacy Day 14 Post-operative(Post-operative Day 14)
- 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)
- 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)
- 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)
- 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)