E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
Hereditary deficiency of Von Willebrand Factor in blood. |
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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 | 14.1 |
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 |
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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 |
Assessment of pharmacokinetics (PK) of rVWF:rFVIII and rVWF and assessment of safety and efficacy of rVWF:rFVIII and rVWF in the treatment of bleeding events in subjects with severe hereditary VWD. |
|
E.2.2 | Secondary objectives of the trial |
• Compare PK parameters of rVWF alone or in combination with rFVIII in subjects with type 3 VWD
• Examine PK parameters of rVWF in subjects with severe VWD or type
2N VWD
• Evaluate hemostatic efficacy, safety, and tolerability of rVWF:rFVIII and rVWF in subjects with VWD receiving the investigational product for the treatment of bleeding episodes
• Evaluate tolerability and safety of rVWF including the development of inhibitory and total binding anti-VWF antibodies and clinically significant changes in laboratory parameters following drug administration
• Assess changes in health-related quality of life (HRQoL) |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Subject has been diagnosed with:
Subject has been diagnosed with:
Type 1 (VWF:RCo < 20 IU/dL) or,
Type 2A (VWF:RCo< 20 IU/dL), 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) or,
Severe VWD with a history of requiring substitution therapy with von
Willebrand factor concentrate to control bleeding.
• Subject, who participates for the treatment for bleeding episodes, has had a minimum of 1 documented bleeds (medical history) requiring VWF coagulation factor replacement therapy duringthe previous12 months prior to enrollment.
• Subject has a Karnofsky score ≥60.
• Subject is at least 18 and not older than 65 years of age at enrollment.
• If female of childbearing potential, subject presents with a negative serum pregnancy test.
• Subject agrees to employ adequate birth control measures for the duration of the study.
• Subject is willing and able to comply with the requirements of the protocol. |
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E.4 | Principal exclusion criteria |
• 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 PT/ international normalized ratio [INR] >1.4).
• Subject has a documented history of a VWF:RCo half-life of <6 hours.
• Subject has a history or presence of a VWF inhibitor at screening.
• Subject has a history or presence of a factor VIII (FVIII) inhibitor with a titer ≥0.4 BU (by Nijmegen assay) or ≥0.6 BU (by Bethesda assay).
• Subject has a known hypersensitivity to any of the components of the study drugs, such as to mouse or hamster proteins.
• Subject has a medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
• Subject has a medical history of a thromboembolic event.
• Subject is HIV positive with an absolute CD4 count <200/mm3.
• Subject has been diagnosed with cardiovascular disease (New York Heart Association [NYHA] classes 1-4).
• Subject has an acute illness (eg, influenza, flu-like syndrome, allergic rhinitis/conjunctivitis, non-seasonal asthma) at screening.
• 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 (eg, presence of otherwise unexplained splenomegaly, history of esophageal varices).
• Subject has been diagnosed with renal disease, with a serum creatinine level ≥2 mg/dL.
• In the judgment of the investigator, subject has another clinically significant concomitant disease (eg, uncontrolled hypertension) that may pose additional risks for the subject.
• Subject has been treated with an immunomodulatory drug, excluding topical treatment (eg, ointments, nasal sprays), within 30 days prior to signing the informed consent.
• Subject is pregnant or lactating at the time of enrollment.
• Subject has participated in another clinical study involving an IP or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an investigational product or investigational device during the course of this study.
• Subject has a history of drug or alcohol abuse within the 2 years prior to enrollment.
• Subject has a progressive fatal disease and/or life expectancy of less than 3 months.
• Subject is identified by the investigator as being unable or unwilling to
cooperate with study procedures.
• 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.
• Subject is in prison or compulsory detention by regulatory and/or juridical order. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Number of subjects with treatment success for treated bleeding episodes. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Overall clinical efficacy rating within 24 hrs of resolution of bleed by investigator. Home treatments will be evaluated at each study visit. Analysis of efficacy will be performed after each study part. |
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E.5.2 | Secondary end point(s) |
1) Efficacy
• Number of treated bleeding episodes with an efficacy rating of
'excellent' or 'good'
• Number of infusions and rVWF:rFVIII and/or rVWF units per bleeding
episode
2) Safety
• Development of inhibitory and total binding anti-VWF antibodies
• Development of inhibitory antibodies to FVIII
• Development of antibodies to Chinese hamster ovary (CHO) proteins,
mouse immunoglobulin G (IgG) and rFurin
• Occurrence of thrombotic events
• Other IP related AEs, such as clinically significant changes in routine
laboratory parameters (hematology and clinical chemistry) and vital
signs
3) Pharmacokinetic
• Area under the plasma concentration/time curve from time 0 to
infinity (AUC0-∞/Dose); area under the plasma concentration/time
curve from time 0 to 96 hours (AUC0-96h/Dose); mean residence time
(MRT); clearance (CL); incremental recovery (IR), elimination phase
half-life (T1/2); volume of distribution at steady state (Vss) of VWF
Ristocetin cofactor (VWF:RCo), VWF antigen (VWF:Ag), VWF
collagenbinding (VWF:CB), and FVIII.
• In vivo recovery (IVR) of VWF:RCo, VWF:Ag and VWF:CB.
• Comparison of intra-subject PK of VWF:RCo, VWF:CB and VWF:Ag at
baseline and after 6 months in a subset of at least 20 subjects with
severe VWD (minimum 6 subjects with type 3 VWD)
4) Exploratory Endpoints
• Subjective hemostatic efficacy rating
• Health-related Quality of Life (HRQoL) measured with two instruments:
- Generic: Physical Component Score (PCS) and Mental Component Score
(MCS) of the Short Form-36 (SF-36)
- Disease-specific: total score of the unvalidated VWD Impact Questionnaire |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
After each study study part. |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
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 | Yes |
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 | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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 | Yes |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Open-label, except for PK50 Arm 1 and Arm 2 (double blinded;randomised) |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 4 |
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 |
Belgium |
Bulgaria |
Canada |
Germany |
India |
Italy |
Japan |
Netherlands |
Poland |
Russian Federation |
Spain |
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 | 2 |
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 | 2 |
E.8.9.2 | In all countries concerned by the trial months | 7 |
E.8.9.2 | In all countries concerned by the trial days | 0 |