VONICOG ALFA for Severe von Willebrand disease

Inclusion criteria

• {"criterion_text":"- The subject has a documented diagnosis of severe VWD (baseline VWF:RCo <20 IU/dL) with a history of replacement therapy with VWF concentrate required to control bleeding and a diagnosis of VWD type 1, type 2 (2A, 2B, 2M, 2N), or type 3. Diagnosis is confirmed, as applicable, by genetic testing and/or by multimer analysis, which may be documented in patient's history or tested at screening.\n- The subject is <18 years of age at the time of screening.\n- Prescreening treatment requirements: a. The subject has been receiving On Demand (OD) therapy with VWF products for at least 12 months (for subjects ≥2 years of age) prior to screening, has experienced at least 1 VWF-treated bleeding event (excluding menorrhagia/heavy menstrual bleeding, as applicable) in the last 12 months, and prophylactic treatment is recommended by the investigator (Prior OD subjects); or b. The subject has been receiving prophylactic treatment with plasma derived (pd)VWF products for at least 12 months prior to screening (for subjects ≥2 years of age) and switching to prophylaxis with vonicog alfa (rVWF) is recommended by the investigator (Switch subjects), c. For subjects <2 years of age, the required duration for prior OD therapy with VWF products or for prior prophylactic treatment with pdVWF products is at least 6 months. Prior OD subjects <2 years of age should have experienced at least 1 VWF-treated bleeding event during the last 6 months based on medical records and be recommended to receive prophylactic treatment by the investigator.\n- For subjects ≥2 years of age, the subject has available records that reliably evaluate type, frequency, severity, and treatment of bleeding episodes for at least 12 months preceding enrollment. For subjects <2 years of age, the subject has available records that reliably evaluate type, frequency, severity and treatment of bleeding episodes for at least 6 months preceding enrollment.\n- If ≥12 years old at the time of screening, the subject has a body mass index (BMI) ≥15 but <40 kg/m2. If ≥2 to <12 years old at the time of screening, the subject has a BMI of ≥5th and <95th percentile (per Centers for Disease Control and Prevention [CDC] clinical charts). For younger subjects who are <2 years old, the \"weight-for-age\" clinical charts (5th to 95th percentile) provided by the CDC should be utilized to ensure the subject has a body weight of ≥5th and <95th percentiles based on gender (for clinical charts provided by CDC, refer to: https://www.cdc.gov/growthcharts/clinical_charts.htm).\n- Female subjects of childbearing potential (ie, had onset of menses/reached puberty) must have a negative blood/urine pregnancy test result at screening and agree to employ highly effective birth control measures (as defined in the protocol) for the duration of their participation in the study.\n- The subject has voluntarily provided assent (if appropriate) and the legally authorized representative(s) has provided informed consent.\n- The subject and/or legally authorized representative is willing and able to comply with the requirements of the protocol, which should also be confirmed based on a prescreening evaluation held between the investigator and the sponsor to ensure no eminent risk is present that could challenge the subject's compliance with the study requirements."}

Exclusion criteria

• {"criterion_text":"- The subject has been diagnosed with pseudo VWD or another hereditary or acquired coagulation disorder other than VWD (eg, qualitative and quantitative platelet disorders or elevated prothrombin time/international normalized ratio less than 1.4).\n- The subject has a platelet count <100,000/mL at screening (because patients with type 2B VWD are considered eligible for this study, for patients with type 2B VWD, platelet count(s) at screening will be evaluated in consultation with the sponsor, taking into consideration historical trends in platelet counts and the investigator's medical assessment of the patient's condition).\n- The subject has been treated with an immunomodulatory drug, excluding topical treatment (eg, ointments, nasal sprays), within 30 days prior to signing the informed consent (or assent, if appropriate).\n- The subject is pregnant or lactating at the time of enrollment.\n- The subject has cervical or uterine conditions causing menorrhagia or metrorrhagia (including infection, dysplasia).\n- The subject has participated in another clinical study involving another 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.\n- The subject has not received OD or prophylactic treatment with a VWF product prior to this study.\n- The subject has a progressive fatal disease and/or life expectancy of less than 15 months.\n- The subject is unable to complete screening procedures and/or comply with the requirements of the protocol in the opinion of the investigator, based on the joint prescreening evaluation held between the investigator and the sponsor.\n- The subject has a history or presence of a VWF inhibitor at screening.\n- The subject has a history or presence of an FVIII inhibitor with a titer ≥0.6 Bethesda units (BU) (by the Nijmegen-modified Bethesda assay) or ≥0.6 BU (by the Bethesda assay).\n- The subject has a known hypersensitivity to any of the components of the study drugs, such as mouse or hamster proteins.\n- The subject has a medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis, mild asthma, food allergies, or animal allergies.\n- The subject has a medical history of a thromboembolic event.\n- The subject is HIV-positive with an absolute helper T cell (CD4) count less than 200/mm3.\n- The subject has been diagnosed with significant liver disease per the investigator's medical assessment of the subject's current condition or medical history or 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.\n- The subject has been diagnosed with renal disease, with a serum creatinine level ≥2.5 mg/dL.\n- The subject 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.\n- The subject is member of the study team or in a dependent relationship with one of the study team members, which includes close relatives (ie, children, partner/spouse, siblings, and parents) as well as employees."}

Primary endpoints

• {"endpoint_text":"- Annualized bleeding rate (ABR) with intra-patient control (on-study compared to historical) for all (both spontaneous and traumatic) bleeding episodes classified by the investigator as either spontaneous or traumatic during prophylactic treatment with vonicog alfa (rVWF)","definition_or_measurement_approach":"ABR measured as annualized bleeding rate on-study compared to each subject's historical ABR (intra-patient control). All bleeding episodes classified by the investigator as spontaneous or traumatic during prophylactic treatment with vonicog alfa (rVWF) are included."}

Secondary endpoints

• {"endpoint_text":"- Safety: a)AEs/serious AEs (SAEs): incidence, severity, causality","definition_or_measurement_approach":"Adverse events and serious adverse events will be recorded and summarised by incidence, severity, and causality."}
• {"endpoint_text":"- b) Occurrence of thromboembolic events","definition_or_measurement_approach":"Recording and incidence of thromboembolic events during study treatment."}
• {"endpoint_text":"- c) Occurrence of hypersensitivity reactions","definition_or_measurement_approach":"Recording and incidence of hypersensitivity reactions during treatment."}
• {"endpoint_text":"- d) Occurrence of infusion-related reactions (IRRs)","definition_or_measurement_approach":"Recording and incidence of infusion-related reactions during or after infusions."}
• {"endpoint_text":"- e) Immunogenicity","definition_or_measurement_approach":"Assessment of immune response to vonicog alfa (e.g., antibody analyses)."}
• {"endpoint_text":"- f) Development of neutralizing antibodies (inhibitors) to VWF and FVIII","definition_or_measurement_approach":"Laboratory testing for development of neutralizing (inhibitor) antibodies against VWF and FVIII."}
• {"endpoint_text":"- g) Development of binding antibodies to VWF and FVIII","definition_or_measurement_approach":"Assessment of binding antibody development to VWF and FVIII through specified immunoassays."}
• {"endpoint_text":"- i) Clinically significant changes in vital signs and clinical laboratory parameters relative to baseline","definition_or_measurement_approach":"Monitoring and comparison of vital signs and laboratory parameters to baseline values to identify clinically significant changes."}
• {"endpoint_text":"- Efficacy of Prophylaxis: a) Categorized ABR defined as 0, >0 to 2, >2 to 5, or >5 during vonicog alfa (rVWF) prophylaxis","definition_or_measurement_approach":"Categorisation of subjects' ABR during prophylaxis into specified bands (0, >0–2, >2–5, >5)."}
• {"endpoint_text":"- b) ABR percent reduction success for Prior OD subjects, defined as at least 25% reduction of ABR for spontaneous bleeding episodes during vonicog alfa (rVWF) prophylaxis relative to the subject's own historical ABR during OD treatment prior to enrollment in this study","definition_or_measurement_approach":"For Prior OD subjects, success defined as ≥25% reduction in spontaneous ABR on-study vs historical OD ABR."}
• {"endpoint_text":"- c) ABR preservation success for plasma-derived (pd)VWF Switch subjects, defined as achieving an ABR for spontaneous bleeding episodes during vonicog alfa (rVWF) prophylaxis that is no greater than the subject's own historical ABR during prophylactic treatment with pdVWF prior to enrollment in this study","definition_or_measurement_approach":"For Switch subjects, success defined as on-study spontaneous ABR ≤ historical prophylactic pdVWF ABR."}
• {"endpoint_text":"- d) ABR for spontaneous bleeding episodes by location of bleeding (gastrointestinal [GI], epistaxis, joint bleeding, menorrhagia/HMB, oral and other mucosa, muscle and soft tissue) historically and while on prophylactic treatment with vonicog alfar (VWF)","definition_or_measurement_approach":"ABR for spontaneous bleeds stratified by anatomical bleed location, compared historical vs on-study."}
• {"endpoint_text":"- e) ABR for bleeding episodes by cause (spontaneous, traumatic [injury related], menstrual bleeding, surgical, unknown) historically and while on prophylactic treatment with vonicog alfa (rVWF)","definition_or_measurement_approach":"ABR stratified by cause of bleed, historical vs on-study."}
• {"endpoint_text":"- g) Total number of infusions and average number of infusions per week during prophylactic treatment with vonicog alfa (rVWF)","definition_or_measurement_approach":"Count of infusions and calculation of mean infusions/week during prophylaxis."}
• {"endpoint_text":"- h) Total weight-adjusted consumption of vonicog alfa (rVWF) per month during prophylactic treatment","definition_or_measurement_approach":"Monthly weight-adjusted product consumption (e.g., IU/kg per month) during prophylaxis."}
• {"endpoint_text":"- Efficacy of on demand (OD) Treatment of Breakthrough Bleeding Episodes: a) Overall hemostatic efficacy rating of breakthrough bleed treatment at resolution of the bleeding episode","definition_or_measurement_approach":"Investigator-assessed overall hemostatic efficacy at bleed resolution for OD-treated breakthrough bleeds."}
• {"endpoint_text":"- b) Number of infusions of vonicog alfa (rVWF) and ADVATE utilized to treat breakthrough bleeding episodes","definition_or_measurement_approach":"Count of infusions of each product used to treat breakthrough bleeds."}
• {"endpoint_text":"- c) Weight-adjusted consumption of vonicog alfa (rVWF) and ADVATE per breakthrough bleeding episode","definition_or_measurement_approach":"Weight-adjusted IU/kg consumption of each product per breakthrough bleed."}
• {"endpoint_text":"- Pharmacokinetic/Pharmacodynamic Endpoints (PK/PD): a) Sparse PK/PD concentrations at scheduled time points for VWF:RCo, VWF:Ag, VWF:CB, VWFGP1bM, and FVIII:C","definition_or_measurement_approach":"Sparse PK/PD sampling at scheduled time points measuring VWF:RCo, VWF:Ag, VWF:CB, VWFGP1bM, and FVIII:C."}
• {"endpoint_text":"- b) Incremental recovery (IR) for VWF:RCo, VWF:Ag, VWF:CB, and VWF:GP1bM","definition_or_measurement_approach":"Calculation of incremental recovery for specified VWF assays."}
• {"endpoint_text":"- c) PK parameters at steady state:t1/2,area under the concentration versus time curve over a dosing interval/area under the concentration versus time curve from 0 to 96 hours,Cmax, ss, time to reach the maximum plasma concentration, volume of distribution at steady state, CLss based on VWF:RCo. The corresponding PD of vonicog alfa (rVWF) as measured in FVIII:C will be assessed using Cmax, ss, Tmax, ss, and AUCtau, ss/AUC0-96hr, ss.","definition_or_measurement_approach":"Assessment of PK parameters at steady state (t1/2, AUC, Cmax, Tmax, Vd, CLss) based on VWF:RCo and PD measures via FVIII:C."}

Methods

• Doctor-to-parent letters distributed via site clinicians (country-specific Dr-to-Parent Letter documents).
• Parent brochures and flyers (country-specific Parent Brochure and Parent Flyer documents) provided at sites and for families.
• Assent guides and age-specific assent forms for children (assent guides/forms for 6-11 years, 10-12, 12-16/12-17, Turning 16/Turning 18 forms) used to inform minors appropriately.
• Site-based recruitment through participating hospitals/haematology centres (listed trial sites in France, Italy, Ireland, Spain).
• Patient recruitment and retention services and Home Health Care support contracted to IQVIA (documented sponsor duty: Home Health Care, Patient Recruitment and Retention).
• Participant reimbursements for incurred costs via Greenphire (sponsor duty: Clinical participants reimbursements for incurred costs).

France

Earliest CTIS Part Ii Submission Date

28-06-2024

Latest Decision Or Authorization Date

08-12-2025

Processing Time Days

528

Number Of Sites

3

Number Of Participants

3

Ireland

Earliest CTIS Part Ii Submission Date

28-06-2024

Latest Decision Or Authorization Date

19-01-2026

Processing Time Days

570

Number Of Sites

1

Number Of Participants

1

Italy

Earliest CTIS Part Ii Submission Date

28-06-2024

Latest Decision Or Authorization Date

04-12-2025

Processing Time Days

524

Number Of Sites

2

Number Of Participants

3

Spain

Earliest CTIS Part Ii Submission Date

28-06-2024

Latest Decision Or Authorization Date

23-08-2024

Processing Time Days

56

Number Of Sites

4

Number Of Participants

4

Primary sponsor

Full Name

Takeda Development Center Americas Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

IQVIA Limited

Responsibilities

Home Health Care, Patient Recruitment and Retention; other operational roles (documented sponsor duties include home health care, recruitment/retention and several other support codes).

Name

Medidata Solutions Inc.

Responsibilities

eCOA

Name

Suvoda LLC

Third parties

• {"country":"Austria","full_name":"Medical University Of Vienna","duties_or_roles":"Neutralizing Ab, VWF:RCo Inhibitor, VWF:CB Inhibitor, VWF:FVIII B Inhibitor","organisation_type":"Educational Institution"}
• {"country":"United States","full_name":"Versiti Wisconsin Inc.","duties_or_roles":"VWF:Innovance (VWF:GP1Bm)","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"France","full_name":"Quipment","duties_or_roles":"Site Equipment","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Germany","full_name":"CheckImmune GmbH","duties_or_roles":"Antibody testing (VWF, FVIII, CHO-Protein ig, Furin ig, Mouse ig)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"eCOA","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Austria","full_name":"Imc University Of Applied Sciences Krems","duties_or_roles":"ADAMTS13 Activity, IgE Ab to VWF","organisation_type":"Educational Institution"}
• {"country":"United States","full_name":"Q Squared Solutions LLC","duties_or_roles":"VWD gene mutation analysis, HLA phenotyping, D-Dimer, P-Selectin","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Q Squared Solutions LLC (Q Squared Solutions LLC listed twice as a laboratory entity)","duties_or_roles":"VWD gene mutation analysis, HLA phenotyping, D-Dimer, P-Selectin","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Q Squared Solutions LLC (as Q Squared Solutions LLC contact for EU)","duties_or_roles":"VWD gene mutation analysis, HLA phenotyping, D-Dimer, P-Selectin","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Labcorp Central Laboratory Services LP","duties_or_roles":"Neutralizing Ab, FVIII Inhibitor Activity, PK Activity: VWF:RCo, VWF:CB, VWF:Ag, FVIII:C","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Greenphire LLC","duties_or_roles":"Clinical participants reimbursements for incured costs","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services SARL","duties_or_roles":"Neutralizing Ab, FVIII Inhibitor Activity, PK Activity: VWF:RCo, VWF:CB, VWF:Ag, FVIII:C","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"MEDILYS Laborgesellschaft mbH","duties_or_roles":"VWF Multimers","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"Home Health Care, Patient Recruitment and Retention; other study operational support duties","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Suvoda LLC","duties_or_roles":"","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Azenta US Inc.","duties_or_roles":"Long Term Sample Storage Laboratory","organisation_type":"Pharmaceutical company"}