| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| severe von Willebrand Disease |
|
| E.1.1.1 | Medical condition in easily understood language |
| severe bleeding disorder (von Willebrand Disease) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10055168 |
| E.1.2 | Term | Von Willebrand's factor deficiency |
| E.1.2 | System Organ Class | 100000004850 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To prospectively evaluate the efficacy of rVWF prophylaxis in children based on the annualized bleeding rate (ABR) with intra-patient control (on-study compared to historical) for all bleeding episodes classified by the investigator as either spontaneous or traumatic while on prophylactic treatment with rVWF. |
|
| E.2.2 | Secondary objectives of the trial |
* To evaluate the long-term safety of rVWF as assessed by adverse events (AEs), including thrombogenicity, hypersensitivity, and immunogenicity, as well as by vital signs and clinical laboratory parameters
* To evaluate additional efficacy of prophylactic treatment with rVWF
* To assess the efficacy of rVWF for On Demand (OD) treatment of breakthrough bleeding episodes (spontaneous and traumatic) while on prophylactic treatment
* To assess pharmacokinetics (PK) and pharmacodynamics (PD) of rVWF following long-term prophylactic treatment |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The subject has a documented diagnosis of severe VWD (baseline VWF:RCo <20 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, as applicable, by genetic testing and/or by multimer analysis, which may be documented in patient’s history or tested at screening.
2. The subject is <18 years of age at the time of screening.
3. 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 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.
4. 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.
5. 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).
6. 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.
7. The subject has voluntarily provided assent (if appropriate) and the legally authorized representative(s) has provided informed consent.
8. 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. |
|
| E.4 | Principal exclusion criteria |
1. 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).
2. The subject has a history or presence of a VWF inhibitor at screening.
3. The subject has a history or presence of an 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 subject has a known hypersensitivity to any of the components of the study drugs, such as mouse or hamster proteins.
5. The subject has a medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis, mild asthma, food allergies, or animal allergies.
6. The subject has a medical history of a thromboembolic event.
7. The subject is human immunodeficiency virus (HIV)-positive with an absolute helper T cell (CD4) count less than 200/mm3.
8. 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.
9. The subject has been diagnosed with renal disease, with a serum creatinine level ≥2.5 mg/dL.
10. 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).
11. 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).
12. The subject is pregnant or lactating at the time of enrollment.
13. The subject has cervical or uterine conditions causing menorrhagia or metrorrhagia (including infection, dysplasia).
14. 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.
15. The subject has not received OD or prophylactic treatment with a VWF product prior to this study.
16. The subject has a progressive fatal disease and/or life expectancy of less than 15 months.
17. The subject is already scheduled for a surgical intervention that will have to be performed while the subject is participating in the study.
18. 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.
19. 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.
20. 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 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 rVWF |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At end of study visit (12 month visit) |
|
| E.5.2 | Secondary end point(s) |
Safety:
• AEs/serious AEs (SAEs): incidence, severity, causality
• Occurrence of thromboembolic events
• Occurrence of hypersensitivity reactions
• Occurrence of infusion-related reactions (IRRs)
• Immunogenicity
• Development of neutralizing antibodies (inhibitors) to VWF and FVIII
• Development of total binding antibodies to VWF and FVIII
• Development of binding antibodies to Chinese hamster ovary (CHO) proteins, mouse immunoglobulin G (IgG) and rFurin
• Clinically significant changes in vital signs and clinical laboratory parameters relative to baseline
Efficacy of Prophylaxis:
• Categorized ABR defined as 0, >0 to 2, >2 to 5, or >5 during rVWF prophylaxis
• ABR percent reduction success for Prior OD subjects, defined as at least 25% reduction of ABR for spontaneous bleeding episodes during rVWF prophylaxis relative to the subject’s own historical ABR during OD treatment prior to enrollment in this study
• ABR preservation success for plasma-derived (pd)VWF Switch subjects, defined as achieving an ABR for spontaneous bleeding episodes during rVWF prophylaxis that is no greater than the subject’s own historical ABR during prophylactic treatment with pdVWF prior to enrollment in this study
• ABR for spontaneous bleeding episodes by location of bleeding (gastrointestinal [GI], epistaxis, joint bleeding, menorrhagia/heavy menstrual bleeding, oral and other mucosa, muscle and soft tissue) historically and while on prophylactic treatment with rVWF
• ABR for bleeding episodes by cause (spontaneous, traumatic [injury related], menstrual bleeding, surgical, unknown) historically and while on prophylactic treatment with rVWF
• ABR for bleeding episodes (spontaneous, traumatic) by treatment given (VWF [VWF alone, VWF+FVIII], antifibrinolytics, no treatment) historically and while on prophylactic treatment with rVWF
• Total number of infusions and average number of infusions per week during prophylactic treatment with rVWF
• Total weight-adjusted consumption of rVWF per month during prophylactic treatment
Efficacy of on demand (OD) Treatment of Breakthrough Bleeding Episodes:
• Overall hemostatic efficacy rating of breakthrough bleed treatment at resolution of the bleeding episode
• Number of infusions of rVWF and ADVATE utilized to treat breakthrough bleeding episodes
• Weight-adjusted consumption of rVWF and ADVATE per breakthrough bleeding episode
Pharmacokinetic/Pharmacodynamic Endpoints (PK/PD):
• Sparse PK/PD concentrations at scheduled time points for VWF:RCo, VWF:Ag, VWF:CB, VWFGP1bM, and FVIII:C
• Incremental recovery (IR) for VWF:RCo, VWF:Ag, VWF:CB, and VWF:GP1bM
• PK parameters at steady state (will be reported separately using a population PK/PD approach): terminal half-life (t1/2), area under the concentration versus time curve over a dosing interval (AUCtau, ss) / area under the concentration versus time curve from 0 to 96 hours (AUC0-96hr, ss), maximum plasma concentration (Cmax, ss), time to reach the maximum plasma concentration (Tmax, ss), volume of distribution at steady state (Vss), and clearance (CLss) based on VWF:RCo. The corresponding PD of rVWF as measured in FVIII:C will be assessed using Cmax, ss, Tmax, ss, and AUCtau, ss/AUC0-96hr, ss. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety Parameters: at every visit
Efficacy of Prophylaxis and will be assessed throughout the study
Efficacy of OD Treatment of Breakthrough Bleeding Episode shall be assessed after the resolution of each bleeding episode
PK/PD samples will be collected on all visits, except screening
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| China |
| Japan |
| United States |
| Austria |
| France |
| Sweden |
| Netherlands |
| Spain |
| Italy |
| Ireland |
| Norway |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 18 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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