| 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 |
|
| 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 |
|
| 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 long-term safety of BIVV001 in previously treated subjects with hemophilia A |
|
| 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 safety and tolerability of BIVV001 treatment.
-To assess the PK of BIVV001 based on the one stage activated partial thromboplastin time (aPTT) and two-stage chromogenic FVIII activity assays (only applicable to Arm B).
-To evaluate the efficacy of BIVV001 for perioperative management
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For participants rolling over into Arm A
• Participants who have completed the studies EFC16923, EFC16925, Arm B or Arm C of the current study, or any other potential BIVV001 study.
• Male or Female
For participants new to BIVV001 (Arm B and C)
• Participants who have severe hemophilia A, defined as <1 IU/dL (<1%) endogenous FVIII activity 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 or 50 EDs for participants aged <6 years.
• Platelet count ≥100 000 cells/μL at screening.
• A participant known to be human immunodeficiency virus (HIV) antibody positive, either previously documented or identified from screening assessments, must have the following results prior to enrollment: CD4 lymphocyte count >200 cells/mm³ and viral load of <400 000 copies/mL
• Male
• Only for Arm B: Chinese participants
• Only for Arm C: planned major surgery within 6 months after Day 1.
|
|
| E.4 | Principal exclusion criteria |
For participants rolling over into Arm A
• Positive inhibitor result, defined as ≥0.6 Bethesda units (BU)/mL.
• Participation in another study.
For participants new to BIVV001 (Arm B and Arm C)
• Any concurrent clinically significant liver disease that, in the opinion of the Investigator, would make the participant unsuitable for enrollment. This may include, but is not limited to cirrhosis, portal hypertension, and acute hepatitis.
• Serious active bacterial, fungal, or viral infection (other than chronic hepatitis or HIV) present within 30 days of screening.
• Other known coagulation disorder(s) in addition to hemophilia A.
• 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 (FVIII) result, defined as ≥0.6 BU/mL at screening.
• Treatment with acetylsalicylic acid (ASA) or antiplatelet agents that are not nonsteroidal anti-inflammatory drugs (NSAIDs) within 2 weeks prior to screening.
• Treatment with NSAIDs greater than the maximum dose specified in the regional prescribing information within 2 weeks prior to screening.
• Systemic treatment within 12 weeks prior to Screening with chemotherapy and/or other immunosuppressive drugs (except for the treatment of hepatitis C virus [HCV] or HIV).
• Emicizumab use within the 20 weeks prior to screening.
• Major surgery within 8 weeks prior to screening.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Number of participants with the occurence of inhibitor development (neuatralizing antibodies detected against factor VIII [FVIII]) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1/ Annual bleeding rate (ABR)
2/ Annualized bleeding rate (ABR) by type of bleed
3/ Annualized bleeding rate (ABR) by location
4 / Percentage of patients who maintain factor VIII (FVIII) above prespecified activity levels
5/ Number of injectons and dose of BIVV0001 to treat a bleeding episode
6/ Percentage of bleeding episode treated with a single injection of BIVV001
7/ Assessment of response to BIVV001 treatment of individual bleeding épisodes
8/ hysician's global assessment (PGA) of participants response to BIVV001
9/ Total annualized BIVV001 consumption
10/ Annulaized joint bleeding rate (AJBR)
11/ Target joint resolution
12/ Change from baseline in Hemophilia Joint Health Score (HJHS)
13/ Change from baseline in PROMIS-SF Physical Function
14/ Change from baseline in Haem-A-QoL total score and physical health score
15/ Change from baselin in Haemo-QoL total score and physical health score
16/ Number of participants with adverse events (AEs) and serious adverse events (SAEs)
17/ Number of particpants with the occurrence of embolic and thrombotic events
18/ PK parameter: Maximum activity (Cmax)
19/ PK parameter: Elimination half-life (t1/2)
20/ PK parameter: Total clearance (CL)
21/ PK parameter: Total clearance at steady state (CLss)
22/ PK parameter: Accumulation index (AI)
23/ PK parameter: Area under the activity time curve (AUC)
24/ PK parameter: Volume of distribution at steady state (Vss)
25/ PK parameter: Mean residence time (MRT)
26/ PK parameter: Incremental recovery (IR)
27/ PK parameter: Trough activity (Ctrough)
28/ PK parameter: Time above FVIII activity levels
29/ Investigators’ or Surgeons’ assessment of participant’s hemostatic response to BIVV001 treatment
30/ Number of injections and dose to maintain hemostasis during perioperative period for major surgery
31/ Total BIVV001 consumption during perioperative period for major surgery
32/ Number and type of blood component transfusions used during perioperative period for major surgery
33/ Estimated blood loss during perioperative period for major surgery |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1/ Baseline to month 48
2/ Baseline to month 48
3/ Baseline to month 48
4/ Baseline to month 48
5/ Month 48
6/ Month 48
7/ Baseline to month 48
8/ Baseline to month 48
9/ Baseline to month 48
10/ Baseline to month 48
11/ Month 48
12/ Baseline to month 48
13/ Baseline to month 48
14/ Baseline to month 48
15/ Baseline to month 48
16/ Baseline to month 48
17/ Baseline to month 48
18/ Baseline to week 52
19/ Baseline to week 26
20/ Baseline to week 26
21/ Baseline to week 26
22/ Baseline to week 26
23/ Baseline to week 26
24/ Baseline to week 26
25/ Baseline to week 26
26/ Baseline to week 52
27/ Baseline to week 52
28/ Baseline to week 26
29/ Baseline to month 48
30/ Baseline to month 48
31/ Baseline to month 48
32/ Baseline to month 48
33/ Baseline to month 48 |
|
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| It is a 3-arm study with single intervention |
|
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 39 |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Canada |
| China |
| Colombia |
| Japan |
| Korea, Republic of |
| Mexico |
| Taiwan |
| United States |
| France |
| Sweden |
| Bulgaria |
| Netherlands |
| Spain |
| Switzerland |
| Germany |
| Greece |
| Italy |
| Belgium |
| Hungary |
| Ireland |
| Turkey |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
End of Study will occur when all of the following criteria have been met:
• At least 200 participants, including participants who were first dosed with BIVV001 when <12 years of age have reached 100 exposed days (ED) and completed a valid inhabitor test after the 100th EDs.
• Completion of arm B and arm C
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 42 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 48 |
Print
