A Study of Recombinant Von Willebrand Factor (rVWF) in Chinese Participants With Von Willebrand Disease (vWD)

Official title

A Clinical Study to Evaluate the Safety, Efficacy and Pharmacokinetics of Recombinant Von Willebrand Factor (rVWF) With or Without ADVATE in the Treatment of Bleeding Episodes in Chinese Subjects Diagnosed With Von Willebrand Disease

Overview

The main aim of this study is to find out if VONVENDI is safe for adult Chinese participants with VWD. The study will also check how well VONVENDI helps control bleeding with or without product ADVATE in the participants who may need elective surgery or dental procedures. In addition, the study will also examine how VONVENDI is processed by the body (known as pharmacokinetic \[PK\]) and how the drug helps the body respond or improve a condition (pharmacodynamic \[PD\]). Participants will receive an initial dose of VONVENDI of 40 to 80 international units per kilogram (IU/kg) of body weight. If a participant's baseline factor VIII (FVIII) level is not high enough to help stop bleeding, VONVENDI will be given along with 30 to 45 IU/kg of ADVATE rFVIII. Participants will be in the study for approximately 14 months. During the study, participants will be followed up at clinics or over telephone calls.

Interventions

• Biological VONVENDI
  VONVENDI is administered by intravenous injection.
• Biological ADVATE
  ADVATE is administered by intravenous injection.

Primary outcome measures

• Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [Time frame: Up to 14 months]
• Number of Participants With TEAEs by Severity [Time frame: Up to 14 months]
• Number of Participants With TEAEs and SAEs by Causality [Time frame: Up to 14 months]
• Number of Participants With Thromboembolic Events and Severe Hypersensitivity Reactions [Time frame: Up to 14 months]
• Number of Participants Who Develop Neutralizing (Inhibitory) Antibodies to VWF and FVIII [Time frame: Up to 14 months]
• Number of Participants Who Develop Binding Antibodies to VWF and FVIII [Time frame: Up to 14 months]
• Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters [Time frame: Up to 14 months]
• Number of Participants With Clinically Significant Abnormalities in 12-lead Electrocardiogram (ECG) [Time frame: Up to 14 months]
• Number of Participants With Clinically Significant Abnormalities in Vital Signs Parameters [Time frame: Up to 14 months]

Secondary outcome measures (12)

• Number of Infusions of VONVENDI With or Without ADVATE per Bleeding Episode [Time frame: Up to 12 months]
• Number of Infusions of ADVATE per Bleeding Episode [Time frame: Up to 12 months]
• Weight-adjusted Consumption of VONVENDI and ADVATE per Bleeding Episode [Time frame: Up to 12 months]
• Time to Resolution of Bleeding Episodes [Time frame: Up to 12 months]
• Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-inf) for VWF: Ristocetin Cofactor (VWF:Rco), VWF: Antigen (VWF:Ag) and VWF: Collagen Binding Capacity (VWF:CB) [Time frame: At baseline: Within 1 hour pre-infusion, 0.25, 0.50, 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours post-infusion]
• Dose Normalized AUC (0-inf) for VWF:RCo, VWF:Ag and VWF:CB [Time frame: At baseline: Within 1 hour pre-infusion, 0.25, 0.50, 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours post-infusion]
• AUC From Time 0 to 96 Hours (AUC0-96h) for VWF:RCo, VWF:Ag and VWF:CB [Time frame: At baseline: Within 1 hour pre-infusion, 0.25, 0.50, 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours post-infusion]
• Dose Normalized AUC(0-96h) for VWF:RCo, VWF:Ag and VWF:CB [Time frame: At baseline: Within 1 hour pre-infusion, 0.25, 0.50, 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours post-infusion]
• Maximum Plasma Concentration (Cmax) for VWF:RCo, VWF:Ag and VWF:CB [Time frame: At baseline: Within 1 hour pre-infusion, 0.25, 0.50, 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours post-infusion]
• Dose Normalized Cmax for VWF:RCo, VWF:Ag and VWF:CB [Time frame: At baseline: Within 1 hour pre-infusion, 0.25, 0.50, 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours post-infusion]
• Time to Reach Maximum Plasma Concentration (Tmax) for VWF:RCo, VWF:Ag and VWF:CB [Time frame: At baseline: Within 1 hour pre-infusion, 0.25, 0.50, 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours post-infusion]
• Mean Residence Time for VWF:RCo, VWF:Ag and VWF:CB [Time frame: At baseline: Within 1 hour pre-infusion, 0.25, 0.50, 1, 3, 6, 12, 24, 30, 48, 72, and 96 hours post-infusion]

Eligibility criteria

Inclusion criteria

• Participant must voluntarily sign an institutional review board (IRB)/independent ethics committee-approved written informed consent form after all relevant aspects of the study have been explained and discussed with the participant.
• Participant has a documented diagnosis of severe VWD (baseline VWF:RCo less than \[<\]20 international units \[IU\]deciliter \[dL\]) with a diagnosis of VWD type verified per the following recommended criteria:

• Type 1 (von Willebrand factor:Ristocetin cofactor activity \[VWF:RCo\] <20 IU/dL and by VWF activity/VWF:antigen \[Ag\] ratio) or,
• Type 2A or type 2B (by VWF activity/VWF:Ag ratio and multimer pattern, with genetics if necessary), type 2N (FVIII:C <10% and genetics), type 2M (by VWF activity/VWF:Ag ratio and multimer pattern) or
• Type 3 (VWF:Ag <=3 IU/dL). Diagnosis is confirmed, when applicable, by genetic testing and/or by multimer analysis.
• Participant is at least 18 years of age at screening.
• Participant is ethnic Chinese and lives in China, including those from Taiwan, Hong Kong, and Macao.
• If female of childbearing potential, participant presents with a negative pregnancy test and agrees to employ adequate birth control measures for the duration of the study.
• Participant is willing and able to comply with the requirements of the protocol.
• Participant has had a minimum of 3 documented bleeds that indicated the need for VWF coagulation factor replacement therapies during the previous 12 months prior to enrollment.

Exclusion criteria

• Participant has been diagnosed with pseudo VWD or another hereditary or acquired coagulation disorder other than VWD (example \[eg\], qualitative and quantitative platelet disorders or elevated prothrombin time \[PT\]/international normalized ratio >1.4).
• Participant has a history or presence of a VWF inhibitor at screening.
• Participant has a documented history of a VWF:RCo half-life of <6 hours.
• Participant has a history or presence of a FVIII inhibitor with a titer greater than or equal to \[>=\] 0.6 Bethesda units per milliliter \[BU/mL\] (by Bethesda assay or Bethesda method with Nijmegen modification).
• Participant has a known hypersensitivity to any of the components of the study drugs, such as to mouse or hamster proteins.
• Participant has a medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
• Participant has a medical history of a thromboembolic event.
• Participant is human immunodeficiency virus (HIV) positive with an absolute cluster of differentiation 4 (CD4) count <200/cubic millimeter (mm\^3).
• Participant has been treated with an immunomodulatory drug, other than antiretroviral chemotherapy eg, α-interferon, or corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 milligram (mg)/day (excluding topical treatment \[eg, ointments, nasal sprays\]), within 30 days prior to signing the informed consent (or assent, if appropriate).
• Participant is pregnant or lactating at the time informed consent is obtained.
• Participant has participated in another clinical study involving an IP, or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study.
• Participant is diagnosed with progressive fatal disease and/or has a life expectancy of less than 15 months.
• Participant is member of the study team conducting this study or in a dependent relationship with one of the study team members. Dependent relationships include close relatives (that is, children, partner/spouse, siblings, parents) as well as employees.
• Participant has an acute illness (eg, influenza, flu-like syndrome, allergic rhinitis/conjunctivitis, nonseasonal asthma) at screening.
• Participant is diagnosed with significant liver disease, as evidenced by, but not limited to, any of the following: serum alanine aminotransferase (ALT) greater than 5 times the upper limit of normal; hypoalbuminemia; portal vein hypertension (eg, presence of otherwise unexplained splenomegaly, history of esophageal varices) or liver cirrhosis classified as Child-Pugh class B or C.
• Participant has been diagnosed with renal disease, with a serum creatinine level >=2.5 milligram per deciliter (mg/dL).
• Participant has a platelet count <100,000/ milliliter (mL) at screening (except for participants with type 2B VWD, whose platelet count\[s\] at screening will be evaluated taking into consideration historical trends in platelet counts and the investigator's medical assessment of the participant's condition).
• Participant has cervical or uterine conditions causing menorrhagia or metrorrhagia (including infection, dysplasia).
• In the judgment of the investigator, the participant has another clinically significant concomitant condition (eg, uncontrolled hypertension) that may pose additional risks for the participant.
• Participant is identified by the investigator as being unable or unwilling to cooperate with study procedures.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 7 centers

• Peking Union Medical College Hospital — Beijing
• Nanfang Hospital Southern Medical University — Guangzhou
• Jinan Central Hospital — Jihan
• Ruijin Hospital Shanghai Jiaotong University School of Medicine — Shanghai
• The First Affiliated Hospital of Soochow University — Suzhou
• Institute of Hematology and Blood Diseases Hospital Chinese Academy of Medical Sciences — Tianjin
• Tongji Hospital Tongji Medical College Huazhong University of Science and Technology — Wuhan

Identifiers

NCT: NCT07129343 · TAK-577-3002

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗