| 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 | 100000011919 | |
| 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 and to compare it to the
subject’s historical ABR for spontaneous bleeding episodes during on-demand treatment. | |
| E.2.2 | Secondary objectives of the trial | Secondary Objectives are
Additional efficacy assessments of prophylactic treatment
Safety and immunogenicity
Pharmacokinetics (PK)
Efficacy of the treatment of bleeding episodes
Efficacy of the treatment of perioperative bleeding management, if
surgery is required | |
| 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. Subject currently receiving on-demand treatment for whom prophylactic treatment is recommended
according to standard of care at the center.
4. Has ≥3 documented spontaneous bleeds requiring VWF treatment during the past 12 months
5. Availability of records to reliably evaluate type, frequency and treatment of bleeding episodes
during 12 months of on-demand treatment prior to enrollment.
6. Subject is ≥18 years old at the time of screening and has a body mass index ≥18 but <30 kg/m2.
7. 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.
8. 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 has received prophylaxis treatment in the 12 months prior to screening (including those
who received treatment once a month for menorrhagia but were not treated for any other bleeds).
3. The subject is currently receiving prophylaxis treatment.
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 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 HIV positive with an absolute Helper T cell (CD4) count 200/mm3.
10. The subject has been diagnosed with significant liver disease as evidenced by any of the following:
serum alanine aminotransferase (ALT) 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 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 identified by the investigator as being unable or unwilling to cooperate with study
procedures.
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 in prison or compulsory detention by regulatory and/or juridical order
21. 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 well
as 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) | | Prospectively recorded ABR for spontaneous (not related to trauma) bleeding episodes during prophylactic treatment with rVWF and the subjects’ historical ABR for spontaneous bleeding episodes during on-demand treatment. | |
| 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) | Efficacy
Number (proportion) of subjects with reduction of ABR for spontaneous
(not related to trauma) bleeding episodes during prophylaxis relative to
the subjects' own historical ABR during on-demand treatment. An ABR
reduction of >25% is considered relevant.
Number (proportion) of subjects with 0 bleeds during prophylactic
treatment with rVWF.
Number of infusions and total weight adjusted consumption of rVWF and
ADVATE (recombinant factor VIII/rFVIII) per month and per year during
prophylactic treatment as well as on-demand treatment.
Safety
Adverse events (AEs)
Incidence of thromboembolic events
Incidence of severe hypersensitivity reactions
Development of neutralizing antibodies to VWF and FVIII
Development of total binding antibodies to VWF and FVIII
Development of antibodies to Chinese hamster ovary (CHO) proteins, mouse immunoglobulin G (IgG) and rFurin.
Pharmacokinetic
Incremental recovery (IR), terminal half-life (T1/2), mean residence time (MRT), area under the curve/dose (AUC/dose), area under moment curve/dose (AUMC/dose), volume of distribution at steady state (Vss) and clearance (CL) based on Von Willebrand factor Ristocetin cofactor activity (VWF:RCo), Von Willebrand factor antigen (VWF:Ag), Von Willebrand collagen binding activity
(VWF:CB) , INNOVANCE VWF Ac (exploratory assay) and time course (72 hours) of FVIII clotting activity (FVIII:C) levels.
Efficacy of the treatment of bleeding episodes
Number of infusions of rVWF and ADVATE (rFVIII) per spontaneous bleeding episode.
Number of infusions of rVWF and ADVATE (rFVIII) per traumatic bleeding episode.
Weight-adjusted consumption of rVWF and ADVATE (rFVIII) per spontaneous bleeding episode.
Weight-adjusted consumption of rVWF and ADVATE (rFVIII) per traumatic bleeding episode.
Overall hemostatic efficacy rating at resolution of bleed
Efficacy of treatment of perioperative bleeding management, if surgery
is required
Intraoperative actual versus predicted blood loss (assessed by the
operating surgeon) at completion of surgery
Intraoperative hemostatic efficacy score on a scale of excellent, good,
moderate or none (assessed by the operating surgeon) at completion of
surgery
For elective surgery: an overall assessment of hemostatic efficacy 24
hours after the last perioperative infusion of rVWF, assessed by the
Investigator
Daily intra- and postoperative weight-adjusted dose of rVWF with or without ADVATE through postoperative day 14. | |
| 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 | No |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 | The trial involves single site in the Member State concerned | Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | | Sweden | | 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 |
