| 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 level 1-2%) hemophilia B. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Previously treated patients (PTPs) 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 | 19.0 |
| 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 | 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 further evaluate the safety, hemostatic efficacy, and immunogenicity of BAX326, and changes in health-related quality of life (HR QoL) in subjects who completed Pivotal Study 250901 or Pediatric Study 251101 or newly recruited, BAX326 naïve subjects, until BAX326 is licensed in the subject’s country or until the accumulation of up to approximately 100 exposure days (EDs) of treatment with BAX326, whichever occurs last but not beyond 31 December 2016 |
|
| E.2.2 | Secondary objectives of the trial |
-To further evaluate safety of BAX 326 in terms of IP-related AEs as well as clinically significant changes in routine laboratory parameters (hematology/clinical chemistry) and vital signs
-To further evaluate the hemostatic efficacy of BAX326 in the prevention and routine prophylaxis of acute bleeding episodes using various dose regimens
-To further evaluate the hemostatic efficacy of BAX326 in the management of acute bleeding episodes
-To further evaluate immunogenicity for up to 100 EDs to BAX326. To monitor incremental recovery (IR) of BAX326 over time
-To evaluate changes in health-related quality of life (HR QoL), Patient Activity Level and health resource use
-Exploratory: To correlate pre-infusion thrombin generation assay (TGA) parameters with preinfusion FIX levels and spontaneous breakthrough bleeds in a subset of subjects receiving twice weekly standard or modified prophylactic treatment, including PK-tailored prophylaxis |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
FOR SUBJECTS TRANSITIONING FROM BAX STUDIES 250901 and 251101
• The subject and/or legal representative has/have voluntartily provided signed informed consent.
• The subject has completed Baxter Pivotal Study 250901 or Pediatric Study 251101.
• Subject has not developed an inhibitory FIX antibody during Baxter clinical study 250901 or Pediatric Study 251101.
• Subject is human immunodeficiency (HIV) negative or is HIV+ with a viral load < 200 particles/μL ~ <400,000 copies/mL
• Subject is immunocompetent as evidenced by a CD4 count ≥ 200 cells/mm3.
• If female of childbearing potential, subject presents with a negative pregnancy test and agrees to continue employing adequate birth control measures for the duration of the study.
• Subject is willing and able to comply with the requirements of the protocol.
FOR NEW SUBJECTS
- Subject and/or legal representative has/have provided signed informed consent.
- Subject is 2 to 70 years old at the time of screening.
- Subject is naïve to BAX326
- Subject has severe (FIX level < 1%) or moderately severe (FIX level 1-2%) hemophilia B (based on the one stage activated partial thromboplastin time (aPTT) assay), as tested at screening at the central laboratory.
- Subject aged ≥ 6 years is previously treated with plasma-derived and/or recombinant FIX concentrate(s) for a minimum of 150 EDs.
- Subject aged < 6 years year is previously treated with plasma-derived and/or recombinant FIX concentrate(s) for a minimum of 50 EDs.
- Subject has no evidence of a history of FIX inhibitors.
- Subject is immunocompetent as evidenced by a CD4 count ≥ 200 cells/mm3 at screening.
- Subject is human immunodeficiency (HIV) negative or is HIV+ with a viral load
< 200 particles/μL ~ < 400,000 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 |
FOR SUBJECTS TRANSITIONING FROM BAX STUDIES 250901 and 251101
• The subject received factor IX product(s) other than BAX 326 upon completion of Baxter pivotal study 250901 or Pediatric Study 251101.
• The subject has been diagnosed with an acquired hemostatic defect other than hemophilia B.
• For subjects transferring from Pivotal Study 250901: The subject’s weight is < 35 kg or > 120 kg.
• The subject’s platelet count is < 100,000/mL.
• The subject has an abnormal renal function (serum creatinine > 1.5 times the upper limit of normal).
• The subject has active hepatic disease with alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels ≥ 5 times the upper limit of normal.
• The subject 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.
• 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 subject’s safety or compliance.
• The subject is planned to take part in any other clinical study, with the exception of BAX 326 Surgery study as described in this protocol, during the course of the Continuation Study.
• The subject is a member of the team conducting this study or is in a dependent relationship with one of the study team members. Dependent relationships include close relatives (i.e., children, partner/spouse, siblings, parents) as well as employees of the investigator or site personnel conducting the study.
FOR NEW SUBJECTS
- Subject has a history of FIX inhibitors with a titer ≥ 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.
- 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.
- Subjects ≥ 12 years of age: Subject’s weight is < 35 kg or > 120 kg
- Subject has a history of allergic reaction, eg, 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 severe chronic liver disease as evidenced by, but not limited to, any of the following: International Normalized Ratio (INR) > 1.4 hypoalbuminemia, portal vein hypertension including presence of otherwise unexplained splenomegaly and history of esophageal varices.
- 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, or recreational drug/alcohol use 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 (eg, 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.
- Subject is a member of the team conducting this study or is in a dependent relationship with one of the study team members. Dependent relationships include close relatives (ie, children, partner/spouse, siblings, parents) as well as employees of the investigator or site personnel conducting the study.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Adverse events possibly or probably related to IP |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Safety and Immunogenicity
• Development of inhibitory and total binding antibodies to FIX.
• Development of antibodies to CHO proteins and rFurin.
• Occurrence of severe allergic reactions, e.g. anaphylaxis.
• Occurrence of thrombotic events
• Clinically significant changes in routine laboratory parameters (hematology and clinical chemistry), and vital signs.
PK
• Incremental recovery (IR) over time
• AUC0-∞ (area under the plasma concentration time curve from time 0
to infinity), IR, T1/2 (elimination phase half-life), MRT (mean residence
time), CL (clearance), Vss (Volume of distribution at steady state)
Hemostatic efficacy
• Treatment of bleeding episodes: number of infusions per bleeding episode, overall hemostatic efficacy rating at resolution of bleed.
• Prophylaxis: annualized bleeding rate.
• Consumption of BAX326:
- Number of infusions and weight-adjusted consumption per month and per year;
- Weight-adjusted consumption per event (prophylaxis and on-demand).
Health Related Quality of Life, Patient Activity Level and Pharmacoeconomic Parameters
Changes in the following HR QoL parameters and health resource use:
• For subjects who are between 2 to 7 years of age:
- Generic: PedsQL™ (Parent-proxy versions: age group 2-4 years and age group 5-7 years)
- Health resource use (hospitalizations, emergency room visits, doctor office visits, etc.)
- Patient Activity Level
• For subjects who are between 8 to 11 years of age:
- Disease-specific: Haemo-QoL, short version
- Generic: PedsQL™ Child version
- Health resource use (hospitalizations, emergency room visits, doctor office visits, etc.)
- Patient Activity Level
• For subjects who are between 12 and 16 years of age the following questioninaires will be used:
- Disease-specific: Haemo-QoL short version
- Generic: PedsQL™
- Health utility: EQ-5D
- General pain assessment through a visual analog scale (VAS)
- Health resource use
- Patient Activity Level
• For subjects aged 17 years and older the following questionnaires will be used:
- Disease-specific: Haem-A-QoL
- Generic: SF-36
- Health Utility: EQ-5D
- General pain assessment through a visual analog scale (VAS)
- Health resource use
- Patient Activity Level |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety and immunogenicity: continuous
Other parameters: End of the trial |
|
| 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 | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunogenicity, hemostatic efficacy |
|
| 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 | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| 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.8.3 |
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 |
| Argentina |
| Brazil |
| Chile |
| Colombia |
| Ireland |
| Italy |
| Japan |
| Korea, Republic of |
| Poland |
| Russian Federation |
| Taiwan |
| Ukraine |
|
| 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 | 5 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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