| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The medical condition to be investigated is Hemophilia B, or Christmas disease. Hemophilia B is a deficiency in the clotting FIX and is a recessively inherited coagulation disorder due to an X-chromosome mutation carried by females and expressed mainly by males, affecting approximately 80,000 people worldwide. |
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| E.1.1.1 | Medical condition in easily understood language |
| Hemophilia B is a genetic disorder that impair the body's ability to control blood clotting or coagulation, which is used to stop bleeding when a blood vessel is broken. |
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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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10053754 |
| E.1.2 | Term | Hemophilia B without inhibitors |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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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 |
The primary objectives of the study are:
• To evaluate the safety and tolerability of rFIXFc
• To evaluate the efficacy of rFIXFc in all treatment arms:
• To evaluate the effectiveness of prophylaxis over on-demand therapy by comparing the annualized number of bleeding episodes between subjects receiving rFIXFc on each prevention regimen (Arm 1 and Arm 2) and subjects receiving rFIXFc on an on-demand regimen (Arm 3)
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| E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
To evaluate and assess the PK parameter estimates of rFIXFc and BeneFIX at
baseline in the Sequential PK subgroup as well as rFIXFc at Week 26 (± 1 week)
To evaluate subjects’ response to treatment
To evaluate rFIXFc consumption
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
To be eligible to participate in this study, candidates must meet the following eligibility criteria at Screening:
1-Able to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local subject privacy regulations. If the subject is younger than 18 years old, then a parent or guardian needs to sign the informed consent form (ICF) and the subject needs to sign the assent form as consistent with local authorities"
2. Male and ≥12 years of age and weigh at least 40 kg
3. Have severe hemophilia B defined as ≤2 IU/dL (≤2%) endogenous FIX activity as determined from the central laboratory at the time of screening. If the screening result is >2%, then the severity of hemophilia B may be confirmed by documented historical evidence from a certified clinical laboratory demonstrating ≤2% FIX:C from the medical record or from a documented genotype known to produce severe hemophilia B;
4. Be a previously treated subject, defined as having at least 100 prior EDs to any recombinant or plasma-derived FIX product (fresh frozen plasma treatment must not be considered in the count of the documented EDs)
5. Have had bleeding events and/or treatment with FIX during the prior 12 weeks, as documented in the subjects’ medical record
6. ≥8 bleeds in the 52 weeks prior to enrollment on the study if currently treating with an on-demand regimen
7. A platelet count ≥100,000 cells/μL
8. Immunocompetent as determined by the investigator’s review of the subject’s medical history
9. Viral load of <400 copies/mL, if human immunodeficiency virus (HIV) antibody positive;
10. An international normalized ratio (INR) <1.40 as defined by the testing laboratory’s normal range.
11. For subjects entering directly into Treatment Arm 4 (Surgery), the subject meets all other eligibility criteria AND requires major elective surgery.
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| E.4 | Principal exclusion criteria |
Candidates will be excluded from study entry if any of the following exclusion criteria exist at Screening:
1. Prior history of, or currently detectable inhibitor as defined by the reporting laboratory (family history of inhibitors will not exclude the subject. A positive inhibitor value is ≥0.6 BU/mL (≥1.0 BU/mL only for laboratories with a historical lower sensitivity cut-off for inhibitor detection of 1.0 BU/mL).
2. Other coagulation disorder(s) in addition to hemophilia B;
3. Prior history of anaphylaxis associated with any FIX or IV immunoglobulin administration
4. Abnormal renal function defined as serum creatinine >2.0 mg/dL
5. Active hepatic disease defined as an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 5 times the upper limit of normal
6. For the Sequential PK subgroup receiving BeneFIX: allergy to Chinese Hamster proteins
7.Any concurrent clinically significant major disease that, in the opinion of the Investigator, makes the subject unsuitable for enrollment
8. Subjects who are unable or unwilling to refrain from taking additional prophylactic doses of FIX prior to sports activity or increased physical activity
9. Concurrent systemic treatment with immunosuppressant drugs within the last 12 weeks prior to the study entry (Exceptions: ribavirin, treatment of hepatitis C virus [HCV] and HIV and/or systemic steroids [a total of 2 pulse treatments within 7 days ≤1mg/kg] and/or inhaled steroids)
10. Current enrollment within the past 30 days in any other clinical study involving investigational drugs.
11. Unable to enter accurate and timely information regarding injections and bleeding episodes into an electronic patient diary and without adequate parental/caregiver support to manage this (per the Investigator’s judgment).
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| E.5 End points |
| E.5.1 | Primary end point(s) |
•Safety and tolerability endpoints include clinically notable changes from baseline in laboratory values and the incidence of AEs, including the incidence of inhibitor development.
•The primary efficacy endpoint is the number of bleeding episodes (spontaneous and traumatic) with rFIXFc per subject annualized over the study period (comparison between Arms 1, 2 vs 3)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Through-out treatment period. |
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| E.5.2 | Secondary end point(s) |
•Assessments of response to treatment with rFIXFc for bleeding episodes, using the 4 point bleeding response scale
•Physicians’ global assessments of subjects’ response to treatment with rFIXFc, using a 4 point scale
•Total annualized rFIXFc consumption per subject
•Dose per injection for Arm 1
•Dosing interval for subjects in Arm 2
•The number of annualized spontaneous bleeding episodes (joint, soft tissue, and muscle) per subject
•The number of annualized joint bleeding episodes (spontaneous and traumatic) per subject
•Time from last injection of rFIXFc to the bleeding episode
•Number of injections and dose per injection of rFIXFc required to stop a bleeding episode (joint, soft tissue, and muscle)
•Quality-of-Life (QoL) via Haemo-QoL or Haem-A-QoL questionnaires for Arms 1 and 2.
For Arm 4:
•Investigators’/Surgeons’ assessments of subjects’ response to surgery with rFIXFc, using a 4-point scale
•Number of injections and dose per injection required to maintain hemostasis during the surgical period
•Estimated blood loss during surgery
•Number of transfusions required for surgery
For Sequential PK Subgroup:
•Pharmacokinetic Endpoints -
Endpoints for pharmacodynamic (PD)/PK assessments will include but not be limited to activity/concentration at maximum (Amax/ Cmax), half-life (t½), clearance (CL), volume of distribution (Vd), area under the curve (AUC), mean residence time (MRT), in vivo recovery, and incremental recovery calculated from the FIX activity/ rFIXFc concentration data. In addition, the time to 1% above baseline will be estimated from the FIX activity profiles. Population PK endpoints are CL and Vd and may include other PK parameters.
•Additional Safety Endpoints -
The following safety measurements will be assessed:
i Vital signs in the PK part of treatment Arm 1
ii Prothrombin split fragments 1+ 2 (F 1+2)
iii D dimer
iv Thrombin-antithrombin complex (TAT)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Through-out treatment period. End-points for surgery sub-group are all collected at the time of surgery. |
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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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| 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 | 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 | Yes |
| 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 | Yes |
| E.8.1.7 | Other | No |
| 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 | 4 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 |
| Brazil |
| Canada |
| China |
| Hong Kong |
| India |
| Japan |
| Poland |
| Russian Federation |
| South Africa |
| United States |
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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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•53 subjects from any treatment arm have completed at least 50 Eds with rFIXFc
•73 subjects from any treatment arm have completed at least 50 EDs with rFIXFc & undergone inhibitor testing or 53 subjects completed at least 50 EDs with no more than 1 subject with positive inhibitor as confirmed by re-testing or 34 subjects have completed at least 50 EDs and undergone inhibitor testing, with no subjects with a positive inhibitor as confirmed by re-testing ( section 16.7.2) |
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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 | 2 |
| 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 | 2 |
| 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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