| 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 |
| Évaluer l’efficacité hémostatique et la sécurité d’emploi du rVWF, avec ou sans ADVATE, dans le traitement et le contrôle d’événements hémorragiques non chirurgicaux chez des patients pédiatriques (< 18 ans) porteurs d’une forme sévère de maladie de Willebrand héréditaire |
|
| 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 rVWF
3. To evaluate the PK parameters of rVWF |
1. Chirurgie programmée ou d’urgence : évaluer l’efficacité hémostatique après la dernière perfusion de rVWF périopératoire
2. Évaluer la sécurité d’emploi du rVWF
3. Évaluer les paramètres PK du 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. The subject and/or the legal representative is willing and able to comply with the requirements of the protocol
Additional inclusion criteria for previously treated subjects and subjects undergoing surgery are as follows:
1. Unable to tolerate or are inadequately responsive to deamino-delta-D-arginine vasopressin
2. The subject has had a minimum of 1 documented bleed requiring VWF coagulation factor replacement therapy during the previous 12 months prior to enrollment and overall historically 3 or more EDs to plasma-derived VWF.
Additional inclusion criterion for previously untreated subjects are as follows:
1. The subject has not received prior VWF coagulation factor replacement therapy |
Les patients qui remplissent TOUS les critères suivants sont éligibles à cette étude :
1. Diagnostic de forme sévère de maladie de Willebrand (c’est-à-dire VWF:RCo < 20 %) :
a. Type 1 (VWF:RCo < 20 UI/dl) ; ou
b. Type 2A (VWF:RCo < 20 UI/dl), Type 2B (diagnostiqué par le génotype), Type 2N (FVIII:C < 10 % et génétique historiquement documentée), Type 2M ; ou
c. Type 3 (VWF:Ag ≤ 3 UI/dl).
2. Âge de 0 à < 18 ans au moment de la sélection
3. Le patient a fourni un assentiment (si applicable) et un ou plusieurs représentants légalement autorisés ont fourni un consentement éclairé
4. Les patientes en âge de procréer doivent présenter un test de grossesse sérique négatif
5. Si applicable, le patient accepte d’utiliser des méthodes contraceptives adéquates pendant la durée de l’étude
6. Le patient et/ou le représentant légal souhaite et est en mesure de respecter les exigences du protocole
Les critères d’inclusion supplémentaires pour les patients précédemment traités et les patients faisant l’objet d’une intervention chirurgicale sont les suivants :
1. Incapacité à tolérer ou réponse inadéquate à la désamino-delta-D-arginine vasopressine
2. Le patient a présenté au minimum une hémorragie documentée nécessitant une thérapie substitutive du facteur de coagulation VWF au cours des 12 mois précédant l’inclusion et au total historiquement au moins 3 jours d’exposition au VWF dérivé du plasma
Les critères d’inclusion supplémentaires pour les patients précédemment non traités sont les suivants :
1. Le patient n’a pas reçu de thérapie substitutive du facteur de coagulation VWF |
|
| 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 hemotherapy (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 or investigational device during the course of this study
15. Subject’s legal representative is a family member or employee of the Investigator |
Les patients qui remplissent l’UN des critères suivants, quel qu’il soit, ne sont pas éligibles à cette étude :
1. Diagnostic de pseudo-maladie de Willebrand ou autre trouble de la coagulation héréditaire ou acquis (par ex. troubles plaquettaires qualitatifs ou quantitatifs ou temps de prothrombine élevé/rapport international normalisé > 1,4)
2. Antécédents ou présence d’un inhibiteur du VWF à la sélection
3. Antécédents ou présence d’un inhibiteur du FVIII avec un titre ≥ 0,4 unité Bethesda (UB) (par dosage Nijmegen) ou ≥ 0,6 UB (par dosage Bethesda)
4. Antécédents documentés d’une demi-vie de VWF:RCo < 6 heures
5. Hypersensibilité connue à l’un des composants du produit à l’étude, tel que les protéines de souris ou de hamster
6. Antécédents médicaux de troubles immunologiques, à l’exclusion d’une rhinite allergique saisonnière/conjonctivite/d’asthme, d’allergies alimentaires ou d’allergies aux animaux
7. Antécédents médicaux d’événement thromboembolique
8. Positivité pour le virus de l’immunodéficience humaine, avec une numération absolue des CD4 < 200/mm3
9. Selon le jugement de l’investigateur, le patient présente une autre maladie concomitante cliniquement significative (par ex. hypertension non contrôlée, cancer) qui pourrait poser des risques supplémentaires pour le patient
10. Diagnostic de maladie hépatique significative prouvée par les paramètres suivants, mais sans s’y limiter : alanine aminotransférase sérique 5 fois supérieure à la limite supérieure de la normale ; hypoalbuminémie ; hypertension portale (par ex., présence de splénomégalie par ailleurs inexpliquée, antécédents de varices œsophagiennes) ou cirrhose hépatique classifiée comme Child B or C
11. Diagnostic de maladie rénale, avec un taux de créatinine sérique ≥ 2,5 mg/dl
12. Traitement médicamenteux immunomodulateur autre qu’une chimiothérapie antirétrovirale (par ex. α-interféron ou corticoïdes à une dose équivalente à de l’hydrocortisone supérieure à 10 mg/jour [à l’exclusion d’un traitement topique {par ex., pommades, pulvérisateurs nasaux}]), au cours des 30 jours précédant la signature du consentement éclairé (ou assentiment, le cas échéant)
13. Pour les patientes, celle-ci est enceinte ou allaite au moment de l’obtention du consentement éclairé (ou de l’assentiment, le cas échéant)
14. Le patient a participé à une autre étude clinique portant sur un PE, autre que le rVWF avec ou sans ADVATE, ou un dispositif expérimental au cours des 30 jours précédant l’inclusion, ou il est prévu qu’il participe à une autre étude clinique portant sur un PE ou un dispositif expérimental au cours de cette étude
15. Le représentant légal du patient est un membre de la famille ou un employé de l’investigateur |
|
| 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
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), 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.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| 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 |
| Austria |
| Belgium |
| Canada |
| Czech Republic |
| Finland |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| 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
|
| LVLS |
| Derniere Visite du Dernier Patient |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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