| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hereditary severe von Willebrand Disease in children |
|
| E.1.1.1 | Medical condition in easily understood language |
| Inherited severe bleeding disorder (von Willebrand Disease) in children. |
|
| 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 | 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 the treatment and control of nonsurgical bleeding events in pediatric subjects (<18 years of age) diagnosed with severe, hereditary VWD. |
|
| E.2.2 | Secondary objectives of the trial |
1. Elective or emergency surgery:to evaluate the of hemostatic efficacy after the last perioperative rVWF infusion.
2.To evaluate the safety of Safety of rVWF.
3. To evaluate the PK of rVWF. |
|
| 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. Diagnosis of severe VWD (defined as VWF:RCo <20%):
a. Type 1 (VWF:RCo <20 IU/dL); or
b. 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
c. Type 3 (VWF:Ag ≤3 IU/dL).
2. Age 0 to <18 years at the time of screening
3. The subject has provided assent (if appropriate) and legally authorized representative(s) has
provided informed consent
4. If female of childbearing potential, subject presents with a negative serum pregnancy test
5. If applicable, subject agrees to employ adequate birth control measures for the duration of the study
6. Subject and/or the legally authorized representative are willing and able to comply with the requirements of the protocol, which should also be confirmed based on a prescreening evaluation held between the Investigator and the Sponsor, to ensure no eminent risk is present that could challenge the subject’s compliance with the study requirements.
Additional inclusion criteria for previously treated subjects as well as for subjects undergoing surgery are as follows:
1. Unable to tolerate or are inadequately responsive to deamino-delta-D-arginine vasopressin (DDAVP)
2. The subject has had a minimum of 1 documented bleed requiring VWF coagulation factor
replacement therapy (ie, treatment with a VWF product) during the previous 12 months prior to enrollment and overall historically
3 or more exposure days (EDs) to VWF replacement therapy.
Additional inclusion criterion for previously untreated subjects are as follows:
1. The subject has not received prior VWF coagulation factor replacement therapy |
|
| 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 prothrombin time/international normalized ratio
>1.4)
2. History or presence of a VWF inhibitor at Screening
3. History or presence of a FVIII inhibitor with a titer ≥0.4 Bethesda units (BU) (by Nijmegen assay)
or ≥0.6 BU (by Bethesda assay)
4. Documented history of a VWF:RCo half-life <6 hours
5. Known hypersensitivity to any of the components of the study drug, such as mouse or hamster
proteins
6. Medical history of immunological disorders, excluding seasonal allergic rhinitis/ conjunctivitis/
asthma, food allergies, or animal allergies
7. Medical history of a thromboembolic event
8. Human immunodeficiency virus positive, with an absolute CD4 count <200/mm3
9. In the judgment of the Investigator, the subject has another clinically significant concomitant
disease (eg, uncontrolled hypertension, cancer) that may pose additional risks for the subject
10. Diagnosis of significant liver disease, as evidenced by, but not limited to, any of the following:
serum alanine aminotransferase 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 B or C
11. Diagnosis of renal disease, with a serum creatinine level ≥2.5 mg/dL
12. Immunomodulatory drug treatment other than anti-retroviral chemotherapy (eg, α-interferon, or corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day (excluding topical treatment [eg, ointments, nasal sprays]), within 30 days prior to signing the informed consent (or assent, if appropriate)
13. If female, subject is pregnant or lactating at the time informed consent (or assent, if appropriate) is obtained.
14. Subject has participated in another clinical study involving an 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 other than rVWF or investigational device during the course of this study
15. Subject’s legal representative is a family member or employee of the Investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary outcome measure is hemostatic efficacy, defined as the number of pediatric subjects with treatment success for rVWF-treated nonsurgical bleeding episodes (using a 4-point scale). Bleeding episode treatment success is defined as a mean efficacy rating
score of <2.5. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Timepoint of assessment is within 24 hrs after onset of each bleeding episode an infusion of study drug, recording is made after resolution of each bleeding episode. |
|
| E.5.2 | Secondary end point(s) |
Efficacy
1. Number of treated nonsurgical bleeding episodes with an efficacy rating of ‘excellent’ or ‘good’.
2. Number of infusions, rVWF units, and ADVATE units (if needed), per bleeding episode.
3. For elective surgery: an overall assessment of hemostatic efficacy 24 hours after the last perioperative infusion of rVWF, assessed by the Investigator (hematologist) on a 4-point scale.
Safety
1. Incidence and severity of adverse events (AEs) by system organ class (SOC) and preferred term.
2. Incidence of thrombotic events.
3. Incidence of severe hypersensitivity reactions.
4. Development of neutralizing antibodies to VWF and FVIII.
5. Development of total binding antibodies to VWF.
6. Development of antibodies to CHO proteins, murine IgG, and rFurin.
Pharmacokinetics (VWF:RCo, VWF:Ag and VWF:CB)
1.Area under the plasma concentration/time curve from 0 to 96 hours post-infusion
(AUC0-96h), area under the plasma concentration/time curve from time 0 to infinity
(AUC0-∞), mean residence time (MRT), maximal plasma concentration (Cmax), time to maximal plasma concentration (Tmax), clearance (CL), incremental recovery
(IR), in-vivo recovery (IVR), elimination phase half-life (T1/2), and volume of
distribution at steady state (Vss) for VWF:RCo.
2. Area under the plasma concentration/time curve from 0 to 96 hours post-infusion
(AUC0-96h) for VWF:Ag and VWF:CB. Point estimates per age cohort will be
presented.
3. Area under the plasma concentration/time curve from 0 to 96 hours post-infusion
(AUC0-96h) for FVIII activity. Point estimates per age cohort will be presented.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Hemostatic Efficacy Assessments for surgeries are performed immediately after surgery by operating surgeon and then 24 hours after last perioperative rVWF infusion, Day 7 and Day 14 by the investigator. (See section 11 of protocol for reference) |
|
| 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 | 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | 3 |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| United States |
| Austria |
| Finland |
| France |
| Poland |
| Netherlands |
| Spain |
| Czechia |
| Germany |
| Italy |
| Belgium |
| Russian Federation |
| Turkey |
| Ukraine |
| United Kingdom |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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