| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Hereditary severe von Willebrand Disease | |
| E.1.1.1 | Medical condition in easily understood language | | Inherited 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 | PT | | E.1.2 | Classification code | 10047715 | | E.1.2 | Term | Von Willebrand's disease | | E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders | |
| 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 | 10010331 - Congenital, familial and genetic disorders | |
| 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 | | The primary objective of this study is to prospectively evaluate the annualized bleeding rate (ABR) for spontaneous bleeding episodes while on prophylactic treatment with rVWF (vonicog alfa) and to compare it to the subject’s historical ABR for spontaneous bleeding episodes. | |
| E.2.2 | Secondary objectives of the trial | Secondary Objectives are to assess
Additional efficacy of prophylactic treatment with rVWF (vonicog alfa)
Safety of rVWF (vonicog alfa), including immunogenicity, thrombogenicity and hypersensitivity
Pharmacokinetics (PK) of rVWF (vonicog alfa) and Pharmacodynamics (PD) of requiredrVWF (vonicog alfa) as measured in FVIII activity
| |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | Subjects who meet ALL of the following criteria are eligible for this study:
1. Subject has a documented diagnosis of severe VWD (baseline VWF:RCo <20 IU/dL) with a history
of requiring substitution therapy with von Willebrand factor concentrate to control bleeding:
a. Type 1 (VWF:RCo <20 IU/dL) or,b. Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by genotype), Type 2M or,
c. Type 3 (VWF:Ag ≤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, subject currently receiving on-demand treatment for whom prophylactic treatment is recommended by the investigator.
4. For pdVWF switch patient group, subject has been receiving prophylactic treatment of pdVWF products for no less than 12 months prior to screening.
5. For on-demand patient group, subject has ≥3 documented spontaneous bleeds (not including menorrhagia) requiring 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 of 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 subjects and is desired (but not a requirement) for on-demand subjects.
7. Subject is ≥18 years old at the time of screening and has a body mass index ≥15 but <40 kg/m2.
8. If female of childbearing potential, subject 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. Subject is willing and able to comply with the requirements of the protocol. | |
| E.4 | Principal exclusion criteria | Subjects who meet ANY of the following criteria are not eligible for this study:
1. The subject has been diagnosed with Type 2N VWD, pseudo VWD, or another hereditary or acquired coagulation disorder other than VWD (e.g., qualitative and quantitative platelet disorders or elevated prothrombin time (PT)/international normalized ratio [INR] 1.4).
2. The subject is currently receiving prophylactic treatment with more than 5 infusions per week.
3. The subject is currently receiving prophylactic treatment with a weekly dose exceeding 240 IU/kg.
4. The subject has a history or presence of a VWF inhibitor at screening.
5. The subject has a history or presence of a FVIII inhibitor with a titer ≥0.4 Bethesda units (BU) (by Nijmegen modified Bethesda assay) or ≥0.6 BU (by Bethesda assay).
6. The subject has a known hypersensitivity to any of the components of the study drugs, such as to mouse or hamster proteins.
7. The subject has a medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
8. The subject has a medical history of a thromboembolic event.
9. The subject is human immunodeficiency virus (HIV) positive with an absolute Helper T cell (CD4) count 200/mm3.
10. The subject has been diagnosed with significant liver disease per investigator’s medical assessment of the subject’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 subject has been diagnosed with renal disease, with a serum creatinine (CR) level ≥2.5 mg/dL.
12. The subject has a platelet count <100,000/mL at screening.
13. The subject 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 subject 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 subject 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 subject has a progressive fatal disease and/or life expectancy of less than 15 months.
18. The subject is scheduled for a surgical intervention.
19. The subject is identified by the investigator as being unable or unwilling to cooperate with study
procedures.
20. 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.
21. The subject is in prison or compulsory detention by regulatory and/or juridical order
22. The subject 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 wellbas employees.
Delay criteria
1. If the subject presents with an acute bleeding episodes or acute illness (e.g., influenza, flu-like
syndrome, allergic rhinitis/conjunctivitis, non-seasonal asthma) the screening visit will be postponed
until the subject has recovered. | |
| E.5 End points |
| E.5.1 | Primary end point(s) | | Annualized bleeding rate (ABR) for spontaneous (not related to trauma) bleeding episodes during prophylactic treatment with rVWF vonicog alfa). | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | | On completion of 12 month prophylactic treatment. | |
| E.5.2 | Secondary end point(s) | Additional efficacy of prophylactic treatment with rVWF (vonicog alfa).
ABR percent reduction success for OD subjects defined as at least 25% reduction of ABR for spontaneous (not related to trauma) bleeding episodes during rVWF (vonicog alfa) prophylaxis relative to the subjects’ own historical ABR during on-demand treatment.
ABR preservation success for pdVWF switch subjects defined as achieving
an ABR for spontaneous bleeding episodes during rVWF (vonicog alfa) prophylaxis that is no greater than the subject’s own historical ABR during prophylactic treatment with pdVWF
Categorized spontaneous ABR defined as 0, 1-2, 3-5, or >5 bleeding episodes during the 12- month prophylactic treatment with rVWF (vonicog alfa)
Total number of infusions and the average number of infusions per week during prophylactic treatment with rVWF (vonicog alfa)
Total weight adjusted consumption of rVWF (vonicog alfa) during prophylactic treatment
Spontaneous ABR by location of bleeding (Gastrointestinal [GI], epistaxis, joint bleeding, menorrhagia, oral and other mucosa, muscle and soft tissue, etc.) while on prophylactic treatment with rVWF (vonicog alfa)
Safety
Adverse events (AEs) : incidence, severity, causality
Thromboembolic events
Hypersensitivity reactions
Development of neutralizing antibodies 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
Pharmacokinetics (PK) and Pharmacodynamics (PD)
PK parameters after a washout for on-demand subjects: incremental recovery (IR), terminal half-life (T1/2), mean residence time (MRT), area under the concentration versus time curve from 0 to infinity (AUC0-∞),area under the concentration versus time curve from 0 to the last measurable concentration (AUC0-tlast), maximum concentration (Cmax), minimum time to reach the maximum concentration (Tmax), volume of distribution at steady state (Vss) and clearance (CL) based on VWF:RCo, Von Willebrand factor antigen (VWF:Ag), Von Willebrand collagen binding activity (VWF:CB).
PD parameters after a washout for on-demand subjects: Cmax, Tmax, and AUC0-tlast as measured in FVIII activity by the 1-stage clotting assay (FVIII:C).
PK parameters at steady state for on-demand and switch subjects: area under the concentration versus time curve from 0 to end of the partial dosing interval (AUC0- tau;ss), maximum concentration during the partial dosing interval (Cmax;ss), minimum time to reach the maximum concentration (Tmax;ss) and minimum concentration during the partial dosing interval (Cmin;ss) based on VWF:RCo, VWF:Ag and VWF:CB. PK parameters at steady state will be assessed shortly after reaching steady state for switch
subjects and at the end of the study for on-demand as well as for switch subjects all based on the longer interval of the irregular dosing intervals employed.
PD parameters at steady state for on-demand and switch subjects: AUC0-tau;ss, Cmax;ss, Tmax;ss, and Cmin;ss as measured in FVIII actvitiy by the 1-stage clotting assay (FVIII:C). PD parameters at steady state will be assessed shortly after reaching steady state for switch subjects and at the end of the study for on-demand as well as for switch subjects all based on the longer interval of the irregular dosing intervals employed.
Time course of FVIII clotting activity (FVIII:C) levels. | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | Efficacy parameters evaluated at end of study.
Safety parameters evaluated within 24 hrs of awareness.
Overall hemostatic efficacy rating at resolution of each bleed within 24 hrs. | |
| 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 | No |
| 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 | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 | | Czech Republic | | Denmark | | Finland | | France | | Germany | | Italy | | Netherlands | | Russian Federation | | Spain | | Turkey | | United Kingdom | | United States | |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
