| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hereditary severe von Willebrand Disease in adult patients who will undergo major and minor elective surgical procedures |
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| E.1.1.1 | Medical condition in easily understood language |
| Inherited severe bleeding disorder (von Willebrand Disease) in adult patients who will undergo major, minor or oral surgical procedures |
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| 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 | 18.0 |
| 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 evaluate the hemostatic efficacy and safety of rVWF with or without ADVATE in subjects (above 18 years) diagnosed with hereditary severe VWD undergoing major and minor elective surgical procedures |
|
| E.2.2 | Secondary objectives of the trial |
Efficacy
• Intraoperative actual versus predicted blood loss at completion of surgery
• Intraoperative hemostatic efficacy score on a scale of excellent, good, moderate or none
• Daily intra- and postoperative weight-adjusted dose of rVWF with or without ADVATE through postoperative day 14
2. Safety
• Adverse Events
• Incidence of thrombotic events
• Incidence of severe allergic reactions
• Incidence of development of inhibitory and total binding antibodies to VWF and inhibitory antibodies to FVIII
• Incidence of development of antibodies to Chinese hamster ovary proteins, murine immunoglobulin G and rFurin
3. Pharmacokinetics
• Area under the plasma concentration versus time curve from 0 to 72 hours postinfusion
• Area under the plasma concentration/time curve from time 0 to infinity,mean residence time, clearance, incremental recovery,elimination phase halflife, Volume of distribution at steady state
4. Exploratory Objectives
• Health-related Quality of Life |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Diagnosis of severe VWD as listed and elective surgical procedure planned:
o VWD with a history of requiring substitution therapy with von Willebrand factor concentrate to control bleeding.
Type 1 (VWF:RCo < 20 IU/dL) or
Type 2A (as verified by multimer pattern), Type 2B (as diagnosed by genotype), Type 2N (FVIII:C<10% and historically documented genetics), Type 2M or
Type 3 (VWF:Ag ≤ 3 IU/dL)
2. If type 3 VWD (VWF Antigen /VWF:Ag ≤ 3 IU/dL), subject has a medical history of at least 20 EDs to VWF/FVIII coagulation factor concentrates (including cryoprecipitate or fresh frozen plasma)
3. If type 1 or type 2 VWD, subject has a medical history of 5 EDs or a past major surgery requiring VWF/FVIII coagulation factor concentrates (including cryoprecipitate or fresh frozen plasma)
4. At least 18 years of age
5. If female of childbearing potential, subject presents with a negative pregnancy test
6. If applicable, subject agrees to employ adequate birth control measures for the duration of the study
7. 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. Diagnosis of pseudo VWD or another hereditary or acquired coagulation disorder (eg qualitative and quantitative platelet disorders or elevated PT/ international normalized ratio [INR] 1.4)
2. History or presence of a VWF inhibitor at screening
3. History or presence of a factor VIII (FVIII) inhibitor with a titer ≥ 0.4 BU (Nijmegen-modified Bethesda assay ) or ≥ 0.6 BU (by Bethesda assay)
4. Known hypersensitivity to any of the components of the study drugs, such as to mouse or hamster proteins
5. Medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies
6. Medical history of a thromboembolic event
7. HIV positive with an absolute CD4 count 200/mm3
8. Platelet count < 100,000/mL
9. Diagnosis of significant liver disease, as evidenced by, but not limited to, 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) or liver cirrhosis classified as Child B or C
10. Diagnosis of renal disease, with a serum creatinine level ≥ 2 .5mg/dL
11. 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
12. Subject is pregnant or lactating at the time informed content is obtained
13. Subject has participated in another clinical study involving an investigational product (IP), other than rVWF with or without ADVATE, 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. (Eligible patients participating in the rVWF Prophy study (071301) may be enrolled).
14. Progressive fatal disease and/or life expectancy of less than 3 months
15. Subject is identified by the investigator as being unable or unwilling to cooperate with study procedures
16. Subject suffers from 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
17. Subject is in prison or compulsory detention by regulatory and/or juridical order
18. Member of the study team conducting this study or in a dependent relationship with one of the study team members. Dependent relationships include close relatives (i.e., children, partner/spouse, siblings, parents) as well as employees
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Overall assessment of hemostatic efficacy will be summarized by the percentage of subjects in each efficacy category (“excellent”, “good”, “moderate” and “none”).
Point estimates and corresponding two-sided exact confidence intervals (CIs) at the 90% confidence level will be calculated for the rate of subjects with an overall assessment of hemostatic efficacy of ‘excellent’ or ‘good’ 24 hours after last perioperative IP infusion or at completion of day 14 visit, whatever occurs earlier |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 24 hours after last perioperative IP infusion or at completion of day 14 visit, whatever occurs earlier |
|
| E.5.2 | Secondary end point(s) |
Intraoperative actual versus predicted blood loss as assessed by the surgeon at completion of surgery will be summarized by the percentage of subjects in each efficacy category (“excellent”, “good”, “moderate”
and “none”).
Point estimates and corresponding two-sided exact confidence intervals (CIs) at the 90% confidence level will be calculated for the rate of hemostatic efficacy assessments with excellent/good outcome performed by the surgeon based on the intraoperative actual versus predicted blood loss.
Intraoperative hemostatic efficacy assessed at completion of surgery by the surgeon will be summarized by the percentage of subjects in each efficacy category (“excellent”, “good”, “moderate” and “none”).
Point estimates and corresponding two-sided exact confidence intervals (CIs) at the 90% confidence level will be calculated for the rate of hemostatic efficacy assessments with excellent/good outcome performed by the surgeon at completion of surgery.
Descriptive statistics (median, quartiles and range) will be used to summarize the actual blood loss expressed as a percentage of the estimated blood loss (EBL).
The summary of average daily and total weight-adjusted doses (average through postoperative day 14) of rVWF with or without:ADVATE per subject will be provided using median, quartiles and range. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Intraoperative
The summary of average daily and total weight-adjusted doses (average through postoperative day 14) |
|
| 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 | 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
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 |
| Australia |
| Austria |
| Czech Republic |
| Germany |
| Italy |
| Netherlands |
| Russian Federation |
| Spain |
| Taiwan |
| Turkey |
| Ukraine |
| 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
|
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| 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 | 5 |
| E.8.9.1 | In the Member State concerned days | |
| 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 |
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