A Phase 3, Prospective, Open-label, Uncontrolled, Multicenter Study on Efficacy and Safety of Prophylaxis With rVWF in Children Diagnosed With Severe Von Willebrand Disease
A Study of Recombinant Von Willebrand Factor (rVWF) (TAK-577) in Children With Severe Von Willebrand Disease (vWD)
Koumura Emiko
Takeda Pharmaceutical Company Limited
1-1, Doshomachi 4-chome, Chuo-ku, Osaka
+81-6-6204-2111
smb.Japanclinicalstudydisclosure@takeda.com
Contact for Clinical Trial Information
1-1, Doshomachi 4-chome, Chuo-ku, Osaka
1-1, Doshomachi 4-chome, Chuo-ku, Osaka
+81-6-6204-2111
smb.Japanclinicalstudydisclosure@takeda.com
Pending
Sept. 04, 2024
24
Interventional
non-randomized controlled trial
open(masking not used)
uncontrolled control
parallel assignment
treatment purpose
1. The participant has a documented diagnosis of severe VWD (baseline von Willebrand factor ristocetin cofactor activity [VWF:RCo] <20 internal units per deciliter [IU/dL]) with a history of substitution 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, when applicable, by genetic testing and/or by multimer analysis, which may be documented in participant's history or at screening.
2. The participant is <18 years of age at the time of screening.
3. Prescreening treatment requirements:
- The participant has been receiving OD therapy with VWF products for at least 12 months (for participants >=2 years of age) prior to screening, has experienced at least 1 VWF-treated bleeding event during (excluding menorrhagia/heavy menstrual bleeding [HMB], as applicable) in the last 12 months, and prophylactic treatment is recommended by the investigator (Prior OD participants); or
- The participant has been receiving prophylactic treatment with pdVWF products for at least 12 months prior to screening (for participants >=2 years of age) and switching to prophylaxis with rVWF is recommended by the investigator (Switch participants).
- For participants <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 participants <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.
4. For participants >=2 years of age, the participant has available records that reliably evaluate type, frequency, severity, and treatment of BEs for at least 12 months preceding enrollment. For participants <2 years of age, the participant has available records that reliably evaluate type, frequency, severity and treatment of BEs for at least 6 months preceding enrollment.
5. If >=12 years old at the time of screening, the participant has a body mass index (BMI) >=15 but <40 kilogram per square meter (kg/m^2). If >=2 to <12 years old at the time of screening, the participant has a BMI of >=5th and <95th percentile (per Centers for Disease Control and Prevention [CDC] clinical charts). For younger participants 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 participant has a body weight of >=5th and <95th percentile based on gender (for clinical charts provided by CDC, refer to: https://www.cdc.gov/growthcharts/clinical_charts.htm).
6. Female participants of childbearing potential (that is, 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 for the duration of their participation in the study.
7. The participant has voluntarily provided assent (if appropriate) and the legally authorized representative(s) has provided informed consent.
8. The participant 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 participant's compliance with the study requirements.
1. The participant has been diagnosed with pseudo VWD or another hereditary or acquired coagulation disorder other than VWD (example, qualitative and quantitative platelet disorders or elevated prothrombin time/international normalized ratio 1.4).
2. The participant has a history or presence of a VWF inhibitor at screening.
3. The participant has a history or presence of an factor VIII (FVIII) inhibitor with a titer >=0.4 Bethesda units (BU) (by the Nijmegen-modified Bethesda assay) or >=0.6 BU (by the Bethesda assay).
4. The participant has a known hypersensitivity to any of the components of the study drugs, such as mouse or hamster proteins.
5. The participant has a medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis, mild asthma, food allergies, or animal allergies.
6. The participant has a medical history of a thromboembolic event.
7. The participant is human immunodeficiency virus (HIV)-positive with an absolute helper T cell (CD4) count <200 per cubic millimeter or microliter (/mm^3).
8. The participant has been diagnosed with significant liver disease per the investigator's medical assessment of the participant'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 (ULN), hypoalbuminemia, portal vein hypertension (example, presence of otherwise unexplained splenomegaly, history of esophageal varices), or liver cirrhosis classified as Child-Pugh class B or C.
9. The participant has been diagnosed with renal disease, with a serum creatinine level >=2.5 milligram per deciliter (mg/dL).
10. The participant has a platelet count <100,000 per milliliter (/mL) at screening (because participants with type 2B VWD are considered eligible for this study, for participants 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 participants condition).
11. The participant has been treated with an immunomodulatory drug, excluding topical treatment (example, ointments, nasal sprays), within 30 days prior to signing the informed consent (or assent, if appropriate).
12. The participant is pregnant or lactating at the time of enrollment.
13. The participant has cervical or uterine conditions causing menorrhagia or metrorrhagia (including infection, dysplasia).
14. The participant 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.
15. The participant has not received OD or prophylactic treatment with a VWF product prior to this study.
16. The participant has a progressive fatal disease and/or life expectancy of less than 15 months.
17. The participant is already scheduled for a surgical intervention that will have to be performed while the participant is participating in the study.
18. The participant 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.
19. 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.
20. The participant is member of the study team or in a dependent relationship with one of the study team members, which includes close relatives (that is, children, partner/spouse, siblings, and parents) as well as employees.
No limit
17age old under
Both
Von Willebrand Disease (VWD)
Cohort 1: Participants With Age >=12 to <18 years
Participants with age greater than or equal to (>=) 12 to less than (<) 18 years who have received on-demand (OD) therapy or prophylactic treatment with a pdVWF product will receive rVWF with an initial dose selected within the range of 40 to 60 international units per kilogram (IU/kg) rVWF, intravenous infusions, twice-weekly for 12 months. Participants may receive rVWF with or without ADVATE intravenous infusions, when indicated (as deemed necessary for breakthrough bleeding episode treatment and perioperative bleeding management).
Cohort 2: Participants With Age >=6 to <12 years
Participants with age >=6 to <12 years who have received OD therapy of VWF product or prophylactic treatment with a pdVWF product will receive rVWF with an initial dose selected within the range of 40 to 60 IU/kg rVWF, intravenous infusions, twice-weekly for 12 months. Participants may receive rVWF with or without ADVATE intravenous infusions, when indicated (as deemed necessary for breakthrough bleeding episode treatment and perioperative bleeding management).
Cohort 3: Participants With Age <6 years
Participants with age <6 years who have received OD therapy of VWF product or prophylactic treatment with a pdVWF product will receive rVWF with an initial dose selected within the range of 40 to 60 IU/kg rVWF, intravenous infusions, twice-weekly for 12 months. Participants may receive rVWF with or without ADVATE intravenous infusions, when indicated (as deemed necessary for breakthrough bleeding episode treatment and perioperative bleeding management).
1. Annualized Bleeding Rate (ABR) for Spontaneous or Traumatic Bleeding Episodes as Assessed by Investigator During Prophylactic Treatment With rVWF
Time Frame: 12 months
ABR during the study compared to historical ABR for each participant for both spontaneous and traumatic bleeding episodes as classified by the investigator during prophylactic treatment with rVWF will be reported.
1. Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
Time Frame: 12 months
2. Number of Participants With TEAEs by Severity
Time Frame: 12 months
3. Number of Participants With TEAEs and SAEs by Causality
Time Frame: 12 months
4. Number of Participants With Thromboembolic Events, Hypersensitivity Reactions and Infusion-Related Reactions (IRR)
Time Frame: 12 months
5. Number of Participants Who Develop Neutralizing Antibodies to VWF and Factor VIII (FVIII)
Time Frame: 12 months
6. Number of Participants Who Develop Total Binding Antibodies to VWF and FVIII
Time Frame: 12 months
7. Number of Participants Who Develop Binding Antibodies to Chinese hamster ovary (CHO) Proteins, Mouse Immunoglobulin G (IgG), and Recombinant Furin (rFurin)
Time Frame: 12 months
CHO, mouse IgG, and rFurin are proteins that may be potentially present in trace amount in final drug product. Number of participants who develop binding antibodies to CHO proteins, mouse IgG, and rFurin will be reported.
8. Number of Participants With Clinically Significant Change From Baseline Values in Vital Sign Parameters
Time Frame: 12 months
Number of participants with clinically significant change from baseline values in vital sign parameters per investigator assessment will be reported.
9. Number of Participants With Clinically Significant Change From Baseline Values in Laboratory Parameters
Time Frame: 12 months
Number of participants with clinically significant change from baseline values in laboratory parameters per investigator assessment will be reported.
10. Number of Participants With Categorized ABR
Time Frame: 12 months
ABR categorized as 0, 0-2, 2-5, or >5 bleeding episodes during rVWF prophylaxis. Number of participants with categorized ABR will be reported.
11. Number of Participants Previously Receiving On-demand Treatment who will Achieve ABR Percent Reduction Success
Time Frame: 12 months
ABR percent reduction success is defined as at least 25% reduction of ABR during rVWF prophylaxis relative to the participant's own historical ABR during OD treatment prior to enrollment in this study. Number of participants previously receiving on-demand treatment who will achieve ABR percent reduction success will be reported.
12. Number of pdVWF Switch Participants With Spontaneous ABR Preservation Success
Time Frame: 12 months
ABR preservation success defined as achieving an ABR for spontaneous bleeding episodes during rVWF prophylaxis that is no greater than the participant's own historical ABR during prophylactic treatment with pdVWF prior to enrollment in this study. Number of pdVWF switch participants with spontaneous ABR preservation success will be reported.
13. Number of Spontaneous ABR During Prophylactic Treatment With rVWF by Location of Bleeding
Time Frame: 12 months
14. ABR for Bleeding Episodes by Bleeding Cause Historically and While on Prophylactic Treatment With rVWF
Time Frame: 12 months
15. ABR for Bleeding Episodes Spontaneous, or Traumatic by Treatment Given Historically and While on Prophylactic Treatment With rVWF
Time Frame: 12 months
16. Total Number of Infusions Administered Per Week During Prophylactic Treatment With rVWF
Time Frame: 12 months
17. Average Number of Infusions Per Week During Prophylactic Treatment With rVWF
Time Frame: 12 months
18. Total Weight Adjusted Consumption of rVWF Per Month During Prophylactic Treatment
Time Frame: 12 months
19. Overall Hemostatic Efficacy Rating of Breakthrough Bleed Treatment at Resolution of the Bleeding Episode
Time Frame: 12 months
20. Number of Infusions of rVWF and ADVATE (rFVIII, octocog alfa) per Bleeding Episode
Time Frame: 12 months
21. Weight-adjusted Consumption of rVWF and ADVATE per Bleeding Episode
Time Frame: 12 months
22. Plasma Level of rVWF based on Von Willebrand Factor: Ristocetin Cofactor (VWF:Rco)
Time Frame: Within 30 minutes pre-infusion and at multiple timepoints (up to 96 hours) post-infusion
23. Plasma Level of rVWF based on Von Willebrand Factor Antigen (VWF:Ag)
Time Frame: Within 30 minutes pre-infusion and at multiple timepoints (up to 96 hours) post-infusion
24. Plasma Level of rVWF based on Von Willebrand Factor Collagen Binding (VWF:CB)
Time Frame: Within 30 minutes pre-infusion and at multiple timepoints (up to 96 hours) post-infusion
25. Plasma Level of rVWF based on Von Willebrand Factor Glycoprotein 1b Binding (VWF:GP1bM)
Time Frame: Within 30 minutes pre-infusion and at multiple timepoints (up to 96 hours) post-infusion
26. Plasma Level of Factor VIII Clotting (FVIII:C)
Time Frame: Within 30 minutes pre-infusion and at multiple timepoints (up to 96 hours) post-infusion
27. Incremental Recovery Based on VWF:Rco
Time Frame: 12 months
28. Incremental Recovery Based on VWF:Ag
Time Frame: 12 months
29. Incremental Recovery Based on VWF:CB
Time Frame: 12 months
30. Incremental Recovery Based on VWF:GP1bM
Time Frame: 12 months
31. Ratio of Area Under the Plasma Level Versus Time Curve From Time 0 to End of the Partial Dosing Interval (AUC0- Tau;ss) and Area Under the Level Versus Time Curve From 0 to 96 Hours (AUC0-96; ss) for VWF:Rco
Time Frame: Within 30 minutes pre-infusion and at multiple timepoints (up to 96 hours) post-infusion
32. Terminal Half-life (T1/2) for VWF:Rco
Time Frame: Within 30 minutes pre-infusion and at multiple timepoints (up to 96 hours) post-infusion
33. Maximum Plasma Level During the Partial Dosing Interval at Steady State (Cmax;ss) for VWF:Rco
Time Frame: Within 30 minutes pre-infusion and at multiple timepoints (up to 96 hours) post-infusion
34. Minimum Time to Reach the Maximum Plasma Level at Steady State (Tmax;ss) for VWF:Rco
Time Frame: Within 30 minutes pre-infusion and at multiple timepoints (up to 96 hours) post-infusion
35. Volume of Distribution at Steady State (Vss) for VWF:Rco
Time Frame: Within 30 minutes pre-infusion and at multiple timepoints (up to 96 hours) post-infusion
36. Clearance (CL) for VWF:Rco
Time Frame: Within 30 minutes pre-infusion and at multiple timepoints (up to 96 hours) post-infusion
37. Maximum Plasma Level During the Partial Dosing Interval at Steady State (Cmax;ss) for FVIII:C
Time Frame: Within 30 minutes pre-infusion and at multiple timepoints (up to 96 hours) post-infusion
38. Minimum Time to Reach the Maximum Plasma Level at Steady State (Tmax;ss) for FVIII:C
Time Frame: Within 30 minutes pre-infusion and at multiple timepoints (up to 96 hours) post-infusion
39. Ratio of Area Under the Plasma Level Versus Time Curve From Time 0 to End of the Partial Dosing Interval (AUC0- Tau;ss) and Area Under the Level Versus Time Curve From 0 to 96 Hours (AUC0-96; ss) for FVIII:C
Time Frame: Within 30 minutes pre-infusion and at multiple timepoints (up to 96 hours) post-infusion
40. Area Under the Level Versus Time Curve From 0 to 96 Hours (AUC0-96; ss) for FVIII:C
Time Frame: Within 30 minutes pre-infusion and at multiple timepoints (up to 96 hours) post-infusion
Takeda Pharmaceutical Company Limited
Nara Medical University Hospital Institutional Review Board
840 Shijo-cho, Kashihara-shi, Nara, Nara
+81-744-22-3051
chiken-jimunara@naramed-u.ac.jp
Approval
Aug. 27, 2024
Yes
Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
