| 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 | 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.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary:
To evaluate the efficacy of rVWF (vonicog alfa) prophylaxis based on the annualized bleeding rate (ABR) of spontaneous (not related to trauma) bleeding episodes in adult and pediatric subjects (aged 12 to <18 years)
during the first 12 months on the study. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary:
To evaluate the long-term safety of rVWF (vonicog alfa) in adult and pediatric subjects as assessed by adverse events (AEs) including thrombogenicity, hypersensitivity, and immunogenicity, as well as by vital signs and clinical laboratory parameters
To evaluate the efficacy of rVWF (vonicog alfa) prophylaxis in adult and pediatric subjects (aged 12 to <18 years) while enrolled in the study
To evaluate the efficacy of different dose regimens for prophylactic treatment in adult and pediatric subjects (aged 12 to <18 years)
To assess the efficacy of rVWF (vonicog alfa) for OD treatment of bleeding episodes (spontaneous and traumatic) in adult and pediatric subjects |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria:
Subjects who have completed Study 071301 or 071102 (or subjects who have completed the surgery in Study 071102 and want to continue to receive OD treatment) and are willing to immediately transition into this study, must
meet the following 2 criteria to be eligible for this study:
1. If female of childbearing potential, has a negative blood/urine pregnancy test at screening and agrees to employ highly effective birth control measures for the duration of the study.
2. Subject and/or legally authorized representative is willing and able to comply with the requirements of the protocol.
New subjects (Cohort 4) who meet the above 2 and ALL the following additional criteria are eligible for this study:
3. Subject has a documented diagnosis of severe VWD (baseline VWF:RCo <20 IU/dL) with a history of requiring substitution therapy with vWF 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).
Diagnosis is confirmed by genetic testing and multimer analysis, documented in patient history or at screening.
4. Subject has been receiving OD therapy with VWF products for at least 12 months, and prophylactic treatment is recommended by the investigator.
5. Subject has ≥3 documented spontaneous bleeds (not including menorrhagia) requiring VWF treatment during
the past 12 months.
6. Subject has available records that reliably evaluate type, frequency, and treatment of bleeding episodes for at
least 12 months preceding enrollment; up to 24 months of retrospective data should be collected if available.
7. Subject is ≥12 years old at the time of screening and has a body mass index ≥15 but <40 kg/m2. |
|
| E.4 | Principal exclusion criteria |
The subject will be excluded from the study if any of the following exclusion criteria are met:
1. The subject has been diagnosed with Type 2N VWD, 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 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 a FVIII inhibitor with a titer ≥0.4 Bethesda units (BU) (by Nijmegen modified Bethesda assay) or ≥0.6 BU (by 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 200/mm3.
8. 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, 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 (CR) level ≥2.5 mg/dL.
10. The subject has a platelet count <100,000/mL at screening.
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 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.
15. The subject has a progressive fatal disease and/or life expectancy of less than 15 months.
16. For new OD subjects, the subject is scheduled for a surgical intervention.
17. The subject is identified by the investigator as being unable or unwilling to cooperate with study procedures.
18. 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.
19. 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint:
Efficacy of Prophylaxis
Spontaneous ABR during prophylaxis treatment with rVWF (vonicog alfa) based on the data collected during the first 12 months of treatment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary Endpoints:
Safety:
AEs/serious adverse events (SAEs): incidence, severity, causality
Occurrence of thromboembolic events
Occurrence of hypersensitivity reactions
Immunogenicity
a. Development of neutralizing antibodies (inhibitors) to VWF and FVIII
b. Development of total binding antibodies to VWF and FVIII
c. 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:
Spontaneous ABR under prophylactic treatment with rVWF (vonicog alfa) while enrolled in the study
Categorized weekly number of infusions defined as 1, 2 or ≥ 3 during prophylactic treatment with rVWF (vonicog alfa)
Categorized spontaneous ABR defined as 0, 1-2, 3-5, or >5 bleeding episodes during rVWF (vonicog alfa) prophylaxis
Time to first bleeding event under each prophylaxis regimen
Spontaneous ABR by location of bleeding (Gastrointestinal [GI], epistaxis, joint bleeding, menorrhagia, oral, muscle and soft tissue, etc.) while on 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
Transfusion free maintenance of hemoglobin and plasma ferritin levels over time
Efficacy of the Treatment of Bleeding Episodes:
Overall hemostatic efficacy rating at the resolution of bleed with respect to the treatment of bleeding episodes for the initial 12 months of study
Number of infusions of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa) utilized to treat bleeding episodes while enrolled in the study
Weight-adjusted consumption of rVWF (vonicog alfa) and ADVATE (rFVIII, octocog alfa) per bleeding episode while enrolled in the study |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
AE will be assessed at each study visit.
thromboembolic events and occurrence of hypersensitivity reactions monitored throughout the study.
All subjects will be tested for binding and neutralizing antibodies to VWF and FVIII at each of
the scheduled visits. Testing will be done prior to IP infusion and with at least a 72-hour washout
period since the last IP infusion.
Efficacy of prophylaxis will be assessed throughout study.
Efficacy for Treatment of Bleeding Episode Investigators will be asked to assess and record hemostatic efficacy after resolution of each bleeding episode. |
|
| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 |
| Austria |
| Belgium |
| Canada |
| Czech Republic |
| Finland |
| France |
| Germany |
| Italy |
| Netherlands |
| Russian Federation |
| Spain |
| 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
|
| The Study Completion Date is defined as the date on which the last subject in the study completes the final protocol-defined assessment(s). This includes the follow-up visit or contact, whichever is later |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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