rVWF IN PROPHYLAXIS

Takeda29 enrolled

Overview

The purpose of this phase 3 study is to investigate the efficacy and safety, including immunogenicity, thrombogenicity and hypersensitivity reactions, as well as pharmacokinetics (PK), health related quality of life (HRQoL) and pharmacoeconomics of prophylactic treatment with recombinant von Willebrand factor (rVWF) (vonicog alfa) in adult participants with severe von Willebrand disease (VWD).

Study Type

INTERVENTIONAL

Allocation

Purpose

PREVENTION

Masking

NONE

Enrollment

Conditions

Von Willebrand Disease

Interventions

von Willebrand factor (Recombinant)BIOLOGICAL

OD participants will receive intravenous (IV) rVWF:RCo at an initial prophylactic dose of 50 +/- 10 International Unit per Kilogram (IU/kg) twice (two infusions) a week for at least 12 months up to 15 months and may be increased up to 80 IU/kg. pdVWF switch cohort participants will receive rVWF:RCo equivalent (± 10%) to the weekly VWF dose received during prophylactic treatment with pdVWF.

Antihemophilic Factor (Recombinant)BIOLOGICAL

During prophylaxis period any bleeding episodes requiring substitution therapy with VWF concentrate to control bleeding will be treated with rVWF with or without ADVATE. Participants will receive rFVIII IV if necessary for OD treatment of breakthrough bleeds or for peri-operative. The dose will be according to the bleeding type and severity and it will be adjusted to the clinical response.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Participant has a documented diagnosis of severe von Willebrand disease (VWD) (baseline Von Willebrand factor: Ristocetin cofactor activity (VWF:RCo) less than (\<) 20 International Units/Deciliter \[IU/dL\]) with a history of requiring substitution therapy with von Willebrand factor concentrate to control bleeding 1. Type 1 (VWF:RCo \<20 IU/dL) or, 2. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by genotype), Type 2M or, 3. Type 3 (Von Willebrand factor antigen (VWF:Ag) less than or equal to \[\< or =\] 3 IU/dL). 2. Diagnosis is confirmed by genetic testing and multimer analysis, documented in patient history or at screening. 3. For on-demand patient group, participant currently receiving on-demand treatment for whom prophylactic treatment is recommended by the investigator. 4. For Plasma derived von Willebrand factor (pdVWF) product switch patient group, participant has been receiving prophylactic treatment of pdVWF products for no less than 12 months prior to screening. 5. For on-demand patient group, participant has greater than or equal to (\>or=) 3 documented spontaneous bleeds (not including menorrhagia) requiring von Willebrand factor (VWF) treatment during the past 12 months. 6. Availability of records to reliably evaluate type, frequency and treatment of bleeding episodes during at least 12 months preceding enrollment. Up to 24 months retrospective data should be collected if available. Availability of dosing and factor consumption during 12 months (up to 24 months) of treatment prior to enrollment is required for pdVWF switch participants and is desired (but not a requirement) for on-demand participants. 7. Participant is \> or = 18 years old at the time of screening and has a body mass index \> or = 15 but \<40 kilogram per meter square (kg/m\^2). 8. If female of childbearing potential, participant presents with a negative blood/urine pregnancy test at screening and agrees to employ adequate birth control measures for the duration of the study. 9. Participant is willing and able to comply with the requirements of the protocol. Exclusion Criteria: 1. The participant has been diagnosed with Type 2N Von Willebrand disease (VWD), pseudo VWD, or another hereditary or acquired coagulation disorder other than VWD (eg qualitative and quantitative platelet disorders or prothrombin time \[PT\]/international normalized ratio \[INR\] greater than \[\>\]1.4). 2. The participant is currently receiving prophylactic treatment with more than 5 infusions per week. 3. The participant is currently receiving prophylactic treatment with a weekly dose exceeding 240 IU/kg. 4. The participant has a history or presence of a VWF inhibitor at screening. 5. The participant has a history or presence of a Factor VIII (FVIII) inhibitor with a titer ≥0.4 Bethesda units (BU) (by Nijmegen modified Bethesda assay) or \> or = 0.6 Bethesda Unit (BU) (by Bethesda assay). 6. The participant has a known hypersensitivity to any of the components of the study drugs, such as to mouse or hamster proteins. 7. The participant has a medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies. 8. The participant has a medical history of a thromboembolic event. 9. The participant is human immunodeficiency virus (HIV) positive with an absolute Helper T cell (CD4) count \<200/ cubic millimeter (mm\^3). 10. The participant has been diagnosed with significant liver disease per investigator's medical assessment of the participant's current condition or medical history or as evidenced by any of the following: serum alanine aminotransferase (ALT) greater than 5 times the upper limit of normal; hypoalbuminemia; portal vein hypertension (e.g., presence of otherwise unexplained splenomegaly, history of esophageal varices). 11. The participant has been diagnosed with renal disease, with a serum creatinine (CR) level \> or = 2.5 milligram per deciliter (mg/dL). 12. The participant has a platelet count \<100,000/ milliliter (mL) at screening. 13. The participant has been treated with an immunomodulatory drug, excluding topical treatment (e.g., ointments, nasal sprays), within 30 days prior to signing the informed consent. 14. The participant is pregnant or lactating at the time of enrollment. 15. Patient has cervical or uterine conditions causing menorrhagia or metrorrhagia (including infection, dysplasia). 16. The participant has participated in another clinical study involving another Investigational product (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. 17. The participant has a progressive fatal disease and/or life expectancy of less than 15 months. 18. The participant is scheduled for a surgical intervention. 19. The participant is identified by the investigator as being unable or unwilling to cooperate with study procedures. 20. The participant has a mental condition rendering him/her unable to understand the nature, scope and possible consequences of the study and/or evidence of an uncooperative attitude. 21. The participant is in prison or compulsory detention by regulatory and/or juridical order. 22. The participant is member of the study team or in a dependent relationship with one of the study team members which includes close relatives (i.e., children, partner/spouse, siblings and parents) as well as employees.

Locations (35)

Outcomes

Primary Outcomes

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

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).

Time frame: Up to 12 months

Secondary Outcomes

Percentage of Prior On-demand Participants Achieved Spontaneous ABR Percent Reduction Success Through Month 12

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.

Time frame: Up to 12 months

Percentage of Switch Participants With Spontaneous ABR Preservation Success Through Month 12

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.

Data from ClinicalTrials.gov

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University of Colorado Health

Loveland, Colorado, United States

University of Florida College of Medicine

Gainesville, Florida, United States

University of Florida College of Medicine

Jacksonville, Florida, United States

Bleeding and Clotting Disorders Institute

Peoria, Illinois, United States

University of Colorado Health

Aurora, Indiana, United States

Indiana Hemophilia and Thrombosis Center

Indianapolis, Indiana, United States

Henry Ford Hospital

Detroit, Michigan, United States

Comprehensive Cancer Center of Wake Forest Unversity

Winston-Salem, North Carolina, United States

Hamilton Health Sciences Centre

Hamilton, Canada

Hôpital Morvan

Brest, Finistere, France

...and 25 more locations

Time frame: Up to 12 months

Number of Participants Based on Categorized Spontaneous ABR (sABR) Through Month 12

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.

Time frame: Baseline through Month 12

Total Number of Infusions Administered Per Participant During Prophylactic Treatment With rVWF Through Month 12

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.

Time frame: Up to 12 months

Average Number of Infusions Per Week Per Participant During Prophylactic Treatment With rVWF Through Month 12

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

Time frame: Up to 12 months

Total Weight Adjusted Consumption of rVWF Per Participant During Prophylactic Treatment Through Month 12

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.

Time frame: Up to 12 months

Number of Treated Spontaneous BEs by Location of Bleeding While on Prophylactic Treatment With rVWF Through Month 12

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.

Time frame: Up to 12 months

Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs

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.

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

Number of Participants Based on Severity of TEAEs

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.

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

Number of Participants With TEAEs Based Causality

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.

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

Number of Participants With Thromboembolic Events

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.

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

Number of Participants With Hypersensitivity Reactions

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.

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

Number of Participants Who Developed Neutralizing Antibodies to Von Willebrand Factor (rVWF) and Factor VIII (FVIII)

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.

Time frame: Baseline through Month 12

Number of Participants Who Developed of Total Binding Antibodies to Von Willebrand Factor (rVWF) and Factor VIII (FVIII)

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.

Time frame: Baseline through Month 12

Number of Participants Who Developed Binding Antibodies to Chinese Hamster Ovary (CHO) Proteins, Mouse Immunoglobulin G (IgG) and/or rFurin

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.

Time frame: Baseline through Month 12

Number of Participants With Clinically Significant Change From Baseline in Vital Signs

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.

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

Number of Participants With Clinically Significant Change From Baseline in Clinical Laboratory Parameters

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

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

Pharmacokinetic (PK) Assessment: Incremental Recovery (IR) Based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco) Activity

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 (\[IU/dL\]/\[IU/kg\]).