E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Previously treated patients (PTPs) with severe (FIX level < 1 %) or moderately severe (FIX ≤ 2 %) hemophilia B. |
|
E.1.1.1 | Medical condition in easily understood language |
Previously teated patients (PTP) 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 | 14.0 |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess BAX 326 pharmacokinetic (PK) parameters and to determine bioequivalence with BeneFIX, to evaluate its hemostatic efficacy, safety, immunogenicity, and changes in health-related quality of life (HRQoL). |
|
E.2.2 | Secondary objectives of the trial |
To compare the PK parameters of BAX 326 with those of BeneFIX
To monitor incremental recovery (IR) of BAX 326 over time
To evaluate the hemostatic efficacy of BAX 326 in the management and prevention of acute bleeding episodes for a period of 6 months.
To evaluate the hemostatic efficacy of BAX326 in the treatment of acute bleeding episodes.
To evaluate the safety in terms of BAX 326 related adverse events, immunogenicity for a minimun of 50 exposure days (EDs), thrombogenicity during the PK parts, 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 is 12 to 65 years old at the time of screening.
Subject and/or legal representative has/have provided signed informed consent.
Subject has severe (FIX level < 1%) or moderately severe (FIX ≤ 2 %) hemophilia B (based on the one stage activated partial thromboplastin time (aPTT) assay), as tested at screening at the central laboratory.
Subject 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 150EDs, s/he can be enrolled if 1) there are 100-150EDs to any FIX product (plasma-derived or recombinant FIX concentrates(s), cryoprecipitate, or fresh frozen plasma) that are not fully documented, and
2) s/he has participated in the Immunine protocol 050901 and accumulated either at lease 50 EDs to Immunine or a total of at least 150 EDs to a plasma-derived and /or recombinant FIX concntrate 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 Sudy 050901 for at least 50 EDs to Immunine priot to enrollment.
Subject is willing to receive prophylactic treatment over a period of 6 months.
If the subject is willing to receive on-demand treatment, the subject has greater than or equal to 12 documented bleeding episodes requiring treatment within 12 months prior to enrollment and is willing to receive on-demand treatment for the duration of participation in this study.
Subject is immunocompetent as evidenced by a CD4 count greater than or equal to 200 cells/mm3.
Subject is human immunodeficiency (HIV) negative or is HIV+ with a viral load of < 200 particles/µL ~<4000,000 copies/mL
If female of childbearing potential, subject presents with a negative pregnancy test and agrees to employ adequate birth control measures for the duration of the study.
Subject is willing and able to comply with the requirements of the protocol. |
|
E.4 | Principal exclusion criteria |
The subject has a history of FIX inhibitors with a titer greater than or equal to 0.6 Bethesda Units (BU) as determined by the Nijmegen modification of the Bethesda assay or the assay employed in the respective local laboratory) at any time prior to screening.
The subject has a detectable FIX inhibitor at screening, with a titer greater than or equal to 0.6 BU as determined by the Nijmegen modification of the Bethesda assay in the central laboratory.
The subject's weight is <35 kg or > 120 kg.
The subject has a history of allergic reation, eg, anaphylaxis, following exposure to FIX concentrate(s).
The subject has known hypersensitivity to hamster proteins or rFurin.
The subject has evidence of an ongoin or recent thrombotic diease, fibrinolysis or disseminted intravasular coagulation (DIC).
The subject has an abnormal renal function (serum creatinine > 1.5 times the upper limit of normal).
The subject has sever chronic liver diease as evidenced by, but not limited to, any of the following: International Normalized Ration (INR) greater than 1.4 hypoalbuminemiaq, portal vein hypertension including presence of otherwise unexplained splenomegaly and histroy of esophageal varices.
The subject has active heptic disease with alanine aminotrasferase (ALT) or aspartate aminotransferase (AST) level greater than or equal to 2 times the upper limit of normal.
The subject has been diagnosed with an inherited or acquired hemostatic defict other than hempholia B.
The subject's platelet count is < 100,000/mL.
The subject has a clinically significant medical, psychiatric, or cognitive illness, or recreational drug/alcohol use that, in the opinion of the investigator, would affect subjec't safety or compliance.
The subject is currently receiving, or is scheduled to receive during the course of the study, an immunomodulating drug (eg. corticosteroid agents at a dose equivalent to hydrocortisone great than 10mg/day, or alpha-interferon) other than anti-retroviral chemotherapy.
The subject has participated in another investigational study within 30days of enrollment. Participation in study 050901 with Immunine is allowed.
The subject is a member of the team conducting this study or is in a dependent relationshep with one of the sutdy team members. Dependent relationships include close relatives (i.e. children, partner/spouse, siblings, parent) as well as employees of the ivestigator or site personnel conducting the study.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
• PK:
o Primary PK: AUC0-72 h/dose (area under the plasma concentration versus time curve from 0 to 72 hours post-infusion)
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
PK: 0.5 - 72 hours post infusion. First dose at study start and 26 weeks of treatment (please refer to protocol page 31). |
|
E.5.2 | Secondary end point(s) |
o Secondary PK: total AUC/dose (area under the plasma concentration/time curve from time 0 to infinity) MRT (mean residence time), CL (clearance), IR, T1/2 (elimination phase half-life), Vss (Volume of distribution at steady state).
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 endpoints
o Consumption of BAX 326: number of infusions and weight-adjusted consumption per month and per year; weight-adjusted consumption per event (prophylaxis and on-demand).
• Safety:
o Development of inhibitory and total binding antibodies to factor IX
o Development of antibodies to Chinese hamster ovary (CHO) proteins and recombinant furin (rFurin)
o Occurrence of severe allergic reactions, eg, anaphylaxis
o Occurrence of thrombotic events and clinically significant changes in thrombogenic markers during the PK parts of the study: prothrombin fragment 1.2 (F 1.2), thrombin-antithrombin III (TAT), D-dimer.
o IP-related AEs
o Clinically significant changes in routine laboratory parameters (hematology and clinical chemistry), and vital signs
• HR QoL and pharmacoeconomic parameters
o Changes in the following HR QoL parameters and health resource use
• For subjects who are between 12 to 16 years of age:
o Disease-specific: Haemo-QoL short version
o Generic: PedsQL™
o Health utility: EQ-5D
o General pain Assessment through a visual analog scale (VAS)
o Health resource use
• For subjects aged 17 years and older:
o Disease-specific: Haemo-A-QoL
o Generic: SF-36
o Health utility: EQ-5D
o General pain assessment through VAS
o Health resource use |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary PK: total AUC0/dose, MRT, CL, IR, T1/2, Vss
Hemostatic efficacy: Number of bleeding episodes beginning within 24 and 48 hours of an infusion as exploratory end point.
Safety: Development of inhibitory and total binding antibodies to FIX etc. (for more details please refer to protocol page 32).
Health related Quality of Life and Health Resource Use Endpoints: please refer to protocol page 32. |
|
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 | 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 |
Immunogenicity, thrombogenicity |
|
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Yes |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
part 1: randomized, controlled, crossover, blinded; part 2,3: open uncontrolled |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 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 |
Argentina |
Brazil |
Chile |
Colombia |
Japan |
Russian Federation |
Ukraine |
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
|
|
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 | 11 |
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 | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |