E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hemophilia A |
A-típusú hemofília |
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E.1.1.1 | Medical condition in easily understood language |
Hemophilia A |
A-típusú hemofília |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060612 |
E.1.2 | Term | Hemophilia A |
E.1.2 | System Organ Class | 100000004850 |
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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 |
- To evaluate the safety of BIVV001 in previously treated pediatric subjects with hemophilia A |
- A BIVV001 biztonságosságának értékelése korábban már kezelt, A-típusú hemofíliában szenvedő gyermekkorú betegek körében |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of BIVV001 as a prophylaxis treatment
- To evaluate the efficacy of BIVV001 in the treatment of bleeding episodes
- To evaluate BIVV001 consumption for prevention and treatment of bleeding episodes
- To evaluate the effect of BIVV001 prophylaxis on joint health outcomes
- To evaluate the effect of BIVV001 prophylaxis on Quality of Life (QoL) outcomes
- To evaluate the efficacy of BIVV001 for perioperative management
- To evaluate the safety and tolerability of BIVV001 treatment
- To assess the pharmacokinetics (PK) of BIVV001
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- A BIVV001 profilaktikus kezelés hatásosságának értékelése
- A BIVV001 hatásosságának értékelése a vérzéses epizódok kezelésében
- A megelőzésre és a vérzéses epizódok kezelésére felhasznált BIVV001 értékelése
- A BIVV001 profilaxis ízületi egészségre kifejtett hatásának a kiértékelése
- Annak értékelése, hogy a BIVV001 profilaxis milyen hatással van az életminőségi (QoL) kimenetelekre
- A BIVV001 hatásosságának értékelése perioperatív kezelésben
- A BIVV001 kezelés biztonságosságának és tolerálhatóságának értékelése
- A BIVV001 farmakokinetikájának (PK) kiértékelése |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Participant must be younger than 12 years of age, at the time of signing the informed consent
- Severe hemophilia A defined as <1 IU/dL (<1%) endogenous FVIII as documented either by central laboratory testing at Screening or in historical medical records from a clinical laboratory demonstrating <1% FVIII coagulant activity (FVIII:C) or a documented genotype known to produce severe hemophilia A.
- Previous treatment for hemophilia A (prophylaxis or on-demand) with any recombinant and/or plasma-derived FVIII, or cryoprecipitate for at least 150 EDs for patients aged 6-11 years and above 50 EDs for patients aged <6 years
- Weight above or equal to 10 kg.
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- A résztvevőnek 12 évesnél fiatalabb korúnak kell lennie a tájékoztatás utáni beleegyező nyilatkozat aláírásának időpontjában
- Súlyos A-típusú hemofília, amelynek meghatározása <1 NE/dl (<1%) endogén FVIII, és ezt vagy a szűrés során végzett központi laboratóriumi vizsgálatokkal igazolták vagy a kórelőzményi dokumentációban megtalálható, egy klinikai laboratórium által korábban végzett <1% FVIII véralvadási aktivitást (FVIII:C) mutató dokumentált eredményként, vagy olyan dokumentált genotípus, amelyről ismert, hogy súlyos A-típusú hemofíliát vált ki.
- A-típusú hemofília korábbi kezelése (profilaxis vagy igény szerint) bármilyen rekombináns és/vagy plazma eredetű FVIII-cal, vagy krioprecipitátummal legalább 150 expozíciós napon át (ED) a 6–11 év közötti betegek körében és 50 ED felett a <6 éves betegek esetén.
- Legalább 10 kg-os testsúly
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E.4 | Principal exclusion criteria |
- History of hypersensitivity or anaphylaxis associated with any FVIII product.
- History of a positive inhibitor (to FVIII) test defined as ≥0.6 BU/mL, or any value greater than or equal to the lower sensitivity cut-off for laboratories with cut-offs for inhibitor detection between 0.7 and 1.0 BU/mL, or clinical signs or symptoms of decreased response to FVIII administrations. Family history of inhibitors will not exclude the participant.
- Positive inhibitor test result, defined as ≥0.6 BU/mL at Screening.
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- Bármely FVIII-kezeléssel kapcsolatos korábbi túlérzékenység vagy anafilaxia.
- Korábbi pozitív inhibitor (FVIII-ra) teszt, amelynek meghatározása ≥0,6 BE/ml, vagy bármely olyan érték, amely egyenlő vagy nagyobb az alacsonyabb érzékenységi küszöbértéknél azon laboratóriumokban, amelyekben a küszöbértékek az inhibitor kimutatására 0,7 és 1,0 BE/ml között vannak, vagy az FVIII alkalmazására adott csökkent válasz klinikai jelei vagy tünetei jelen vannak. Az inhibitorok családi előzménye nem zárja ki a résztvevőt.
- Pozitív inhibitorteszt eredmény, ≥0,6 BE/ml-ként meghatározva a szűrésnél.
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E.5 End points |
E.5.1 | Primary end point(s) |
Occurrence of inhibitor development |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1 - Annualized bleeding rate (ABR)
2 - Annualized bleeding rate (ABR) by type of bleed
3 - Annualized bleeding rate (ABR) by location of bleed
4 - Percentage of participants who maintain FVIII activity above prespecified levels
5 - Number of injection and dose of BIVV001 to treat a bleeding episode
6 - Percentage of bleeding episodes treated with a single injection of BIVV001
7 - Assessment of response to BIVV001 treatment of individual bleeding episodes
8 - Physician’s global assessment of the participant’s response based on BIVV001 treatment
9 - Total annualized BIVV001 consumption
10 - Annualized Joint Bleeding Rate (AJBR)
11 - Target joint resolution
12 - Change in Hemophilia Joint Health Score (HJHS) total score and domain scores
13 - Changes in Haemophilia Quality of Life Questionnaire for Children (Haemo-QoL) total score
14 - Changes in Haemophilia Quality of Life Questionnaire for Children (Haemo-QoL) physical health domain scores
15 - Investigators’ or Surgeons’ assessment of participant’s hemostatic response to BIVV001 treatment
16-- Number of injections and dose to maintain hemostasis during perioperative period for major surgery
17 - Total BIVV001 consumption during perioperative period for major surgery
18 - Number of blood component transfusions used during perioperative period for major surgery
19 - Type of blood component transfusions used during perioperative period for major surgery
20 - Estimated blood loss during perioperative period for major surgery
21 - Number of participants with occurence of adverse events (AEs) and serious adverse events (SAEs)
22 - Number of participants with occurrence of embolic and thrombotic events
23 - PK parameter: Maximum activity (Cmax)
24 - PK parameter: Elimination half-life (t1/2)
25 - PK parameter: Total clearance (CL)
26 - PK parameter: Total clearance at steady state (CLss)
27 - PK parameter:dose-normalized area under the activity-time curve (DNAUC)
28 - PK parameter: Area under the activity time curve (AUC)
29 - PK parameter: Volume of distribution at steady state (Vss)
30 - PK parameter: Mean residence time (MRT)
31 - PK parameter: Incremental recovery (IR)
32 - PK parameter: Trough activity (Ctrough)
33 - PK parameter: Time above predefined FVIII activity levels
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1 to 6, 8 to 10 , 12 to 23, 31, 32 : Baseline to 52 weeks
7 : 52 weeks
11 : At week 52
24 to 30, 33: Baseline (day 1)
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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 | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 |
Turkey |
Belgium |
Canada |
Germany |
Hungary |
Ireland |
Italy |
Netherlands |
Spain |
Sweden |
Switzerland |
Taiwan |
United Kingdom |
United States |
France |
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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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End of Study will occur when both of the following criteria have been met:
• At least 50 participants (25 subjects <6 years of age and 25 subjects 6 to <12 years of age) have reached 50 exposure days (EDs) and have completed a valid inhibitor test after the 50th ED.
• 24 participants (12 subjects <6 years of age and 12 subjects 6 to <12 years of age) in the PK subgroup have completed the BIVV001 PK profile with adequate estimate of terminal t1/2.
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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 | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |