| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pediatric previously treated patients (PTPs) with severe (FIX level < 1%) or moderately severe (FIX level ≤ 2%) hemophilia B. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Previously treated children with severe or moderately severe hemophilia B. |
|
| 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 | LLT |
| E.1.2 | Classification code | 10018939 |
| E.1.2 | Term | Haemophilia B (Factor IX) |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| 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 assess BAX326 pharmacokinetic (PK) parameters, to evaluate its hemostatic efficacy, safety, immunogenicity, and changes in health-related quality of life (HR QoL) in pediatric patients. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the PK parameters of BAX326 in pediatric PTPs < 12 years of age
• To monitor incremental recovery (IR) of BAX326 over time
• To evaluate the hemostatic efficacy of BAX326 in the management and prevention of acute bleeding episodes for a period of 6 months
• To evaluate safety in terms of immunogenicity for a minimum of 50 exposure days (EDs), the occurrence of thrombotic events, as well as clinically significant changes in routine laboratory parameters (hematology/clinical chemistry) and vital signs.
• To evaluate changes in HR QoL and health resource use
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Subject and/or legal representative has/have voluntarily provided signed informed consent
• Subject has severe (FIX level < 1%) or moderately severe (FIX level ≤ 2%) hemophilia B based on the one-stage activated partial thromboplastin time (aPTT) assay, as determined by the central laboratory
• Subject is < 12 years old at the time of screening
• Subject 6 to <12 years of age is previously treated with plasma-derived and/or recombinant FIX concentrate(s) for a minimum of 150 EDs (based on the subject’s medical records).
If a subject does not have a verifiable, documented history of 150 EDs, s/he can be enrolled if the following criteria are met:
1) there are an estimated 100 - 150 EDs to any FIX product (plasma-derived or recombinant FIX concentrate(s), prothrombin complex concentrate PCC or fresh frozen plasma FFP that are not fully documented (assumption based on the severity of disease and treatment history), and
2) s/he has participated in Immunine Study 050901 and accumulated either at least 50 EDs to Immunine or a total of at least 150 EDs to a plasma-derived and/or recombinant FIX concentrate prior to enrollment
• Subject < 6 years of age is previously treated with plasma-derived and/or recombinant FIX concentrate(s) for > 50 EDs (based on the subject’s medical records).
If a subject does not have a verifiable, documented history of >50 EDs, s/he can be enrolled if the following criteria are met:
1) there are approximately 20 - 50 EDs to any FIX product (plasma-derived or recombinant FIX concentrate(s), PCC or FFP) that are not fully documented, and
2) s/he has participated in Immunine Study 050901 and accumulated a minimum of 30 EDs to Immunine or a total of > 50 EDs to a plasma-derived and/or recombinant FIX concentrate prior to enrollment
• Subject has no evidence of a history of FIX inhibitors (based on the subject’s medical records). If a verifiable, documented history is unavailable, the subject can be enrolled if s/he has participated in Study 050901 for at least 30 EDs (< 6 years of age) or at least 50 EDs (6 to < 12 years of age) to Immunine prior to enrollment
• Subject and/or legal representative accepts prophylactic treatment over a period of 6 months
• Subject is immunocompetent as evidenced by a CD4 count ≥ 200 cells/mm3
• Subject is human immunodeficiency (HIV) negative or is HIV+ with a viral load < 200 particles/μL ~ < 400,000 copies/mL
• Subject and/or the legal representative is willing and able to comply with the requirements of the Protocol |
|
| E.4 | Principal exclusion criteria |
• Subject has a history of FIX inhibitors with a titer ≥ 0.6 BU (as determined by the Nijmegen modification of the Bethesda assay or the assay employed in the respective local laboratory with the corresponding detection limit) at any time prior to screening
• Subject has a detectable FIX inhibitor at screening, with a titer ≥ 0.6 BU as determined by the Nijmegen modification of the Bethesda assay in the central laboratory
• Subject has a history of allergic reaction, e.g. anaphylaxis, following exposure to FIX concentrate(s)
• Subject has a known hypersensitivity to hamster proteins or rFurin
• Subject has evidence of an ongoing or recent thrombotic disease, fibrinolysis or disseminated intravascular coagulation (DIC)
• Subject has an abnormal renal function (serum creatinine >1.5 times the upper limit of normal)
• Subject has an International Normalized Ratio (INR) >1.4
• Subject has active hepatic disease with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels > 5 times the upper limit of normal
• Subject has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia B
• Subject’s platelet count is < 100,000/mL
• Subject has a clinically significant medical, psychiatric, or cognitive illness, that, in the opinion of the Investigator, would affect subject’s safety or compliance
• Subject is currently receiving, or is scheduled to receive during the course of the study, an immunomodulating drug (e.g. corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day, or α-interferon) other than anti-retroviral chemotherapy
• Subject has participated in another investigational study within 30 days of enrollment. However, participation in Study 050901 with Immunine is allowed. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • All AEs possibly or probably related to BAX326 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
• PK:
o Area under the plasma concentration versus time curve from 0 to 72 hours post-infusion (AUC0-72 h/dose), total AUC/dose, mean residence time (MRT), clearance (CL), incremental recovery (IR), elimination phase half-life (T1/2), volume of distribution at steady state (Vss)
o IR over time
• Hemostatic efficacy:
o Treatment of bleeding episodes: number of infusions per bleeding episode, overall hemostatic efficacy rating at resolution of bleed
o Prophylaxis: annualized bleeding rate
o Prophylaxis: number of bleeding episodes beginning within 24 and 48 hours of an infusion as exploratory outcome measures
o Consumption of BAX326: number of infusions and weight-adjusted consumption per month and per year; weight-adjusted consumption per event
• Safety and immunogenicity:
o Development of inhibitory and total binding antibodies to FIX
o Occurrence of severe allergic reactions, e.g. anaphylaxis
o Occurrence of thrombotic events
o Clinically significant changes in routine laboratory parameters (hematology and clinical chemistry) and vital signs
o Development of antibodies to Chinese hamster ovary (CHO) proteins and recombinant furin (rFurin)
• Changes in the following HR QoL parameters and health resource use
For subjects who are between 2 to 7 years of age:
o Generic: PedsQL™ (Parent-proxy versions: age group 2-4 years and age group 5-7 years)
o Health resource use (hospitalizations, emergency room visits, doctor office visits, etc.)
For subjects who are between 8 to 11 years of age:
o Disease-specific: Haemo-QoL, short version
o Generic: PedsQL™ Child version
o Health resource use (hospitalizations, emergency room visits, doctor office visits, etc.)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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) | Yes |
| 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 | 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 | 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.8.3 |
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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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 |
| Bulgaria |
| Czech Republic |
| Germany |
| India |
| Poland |
| Romania |
| Russian Federation |
| 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
|
• If two or more subjects develop a high titer inhibitory antibody > 5 Bethesda Unit (BU) confirmed by the central laboratory, or if two or more subjects develop anaphylaxis following exposure to BAX326, the recruitment will be halted.
• The study may be stopped following any of the planned interim safety reviews or at any time by the Sponsor based on DSMC recommendations in case of unacceptable risks to subjects, such as increased inhibitor development, thrombotic events, or anaphylaxis.
|
|
| 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 | 6 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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