E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Hemophilia B is an X-linked recessive inherited bleeding disorder resulting from a deficiency of coagulation factor IX (FIX), a coagulation factor central to the process of blood coagulation |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060614 |
E.1.2 | Term | Hemophilia B (Factor IX) |
E.1.2 | System Organ Class | 100000004850 |
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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 |
To evaluate the safety of rIX-FP as measured by new cases of inhibitors against FIX in subjects, including previously untreated patients (PUPs), with severe hemophilia B. Pharmacokinetic parameters in PUPs will also be investigated. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are:
• To evaluate the efficacy of rIX-FP routine prophylaxis when administered at various treatment intervals.
• To compare the efficacy of rIX-FP routine prophylaxis between 2 different treatment intervals and versus on-demand treatment.
• To further evaluate the safety of rIX-FP.
• To evaluate the efficacy of treatment for bleeding episodes in PUPs.
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Surgery substudy: Subjects (other than those in France) may participate in a surgical substudy in which rIX-FP may be administered before, during and after surgery. The substudy will examine the safety and efficacy of rIX-FP in patients with hemophilia B who are undergoing surgery. The objectives of the substudy are to evaluate the efficacy of rIX-FP in the prevention and control of bleeding in patients with severe hemophilia B during surgical procedures and to evaluate the safety of rIX-FP during the intraoperative and postoperative periods.
Substudy: Subjects may participate in a substudy to examine the safety and PK of SC administration of rIX-FP |
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E.3 | Principal inclusion criteria |
Main study inclusion criteria:
For previously treated subjects, either:
• Completed a CSL-sponsored rIX-FP (CSL654) study, including study CSL654_3001 [NCT01496274] or study CSL654_3002 [NCT01662531].
Or:
• Scheduled to have a major non-emergency surgery within approximately 8 weeks from the anticipated date of receiving the first rIX-FP injection.
• Not previously completed a CSL-sponsored rIX-FP lead-in study.
• Male, 12 to 70 years of age.
• Documented severe hemophilia B (FIX activity of ≤ 2%), or confirmed at screening by the central laboratory.
• Subjects who have received FIX products (plasma-derived and / or recombinant FIX) for > 150 EDs, confirmed by their treating physician.
• No confirmed history of FIX inhibitor formation at screening by the central laboratory
For previously untreated subjects:
• Male, up to 18 years of age.
• Documented severe hemophilia B (FIX activity of ≤ 2%), or confirmed at screening by the central laboratory.
• Never previously been treated with FIX clotting factor products (except previous exposure to blood components).
• No confirmed history of FIX inhibitor formation
Surgery substudy inclusion criterion:
• Must require non-emergency surgery
Subcutaneous substudy inclusion criteria:
• Male, at least 18 years of age.
• Subjects currently enrolled in Study CSL654_3003
• Subjects who have received rIX-FP for ≥ 100 EDs (single-dose cohorts) or for ≥ 50 EDs (repeated-dose cohort) |
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E.4 | Principal exclusion criteria |
Main study exclusion criteria:
• Currently receiving a therapy not permitted during the study.
• Any issue that, in the opinion of the investigator, would render the subject unsuitable for participation in the study.
For subjects who have previously completed a CSL-sponsored rIX-FP study:
• Unwilling to participate in the study for a total of 100 exposure days.
For subjects requiring major non-emergency surgery who have not previously completed a CSL-sponsored rIX-FP lead-in study:
• Known hypersensitivity (ie, allergic reaction or anaphylaxis) to any FIX product or hamster protein.
• Known congenital or acquired coagulation disorder other than congenital FIX deficiency.
• Currently receiving IV immunomodulating agents such as immunoglobulin or chronic systemic corticosteroid treatment.
• Low platelet count, kidney or liver disease.
• Human immunodeficiency virus positive with a CD4 count < 200/mm3.
For previously untreated subjects:
• Known congenital or acquired coagulation disorder other than congenital FIX deficiency (except for vitamin K deficiency of the newborn).
• Known kidney or liver dysfunction or any condition which, in the investigator’s opinion, place the patient at unjustifiable risk.
The surgical sub-study does not have any additional exclusion criteria, although subject(s) in France will not be eligible for the surgery sub-study.
Subcutaneous substudy exclusion criteria:
• Intravenous use of rIX-FP within 14 days of subcutaneous administration of rIX-FP.
•Life-threatening bleeding episode or major surgery during the 3 months prior to substudy entry
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Main study: Total number of subjects who develop inhibitors against factor IX (FIX);
2. Surgery substudy: Investigator’s overall clinical assessment of hemostatic efficacy for surgical prophylaxis;
3. Incremental recovery in previously untreated patients (PUPs).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
to 1: Main study: Approximately 5 years;
to 2: Surgery substudy: Immediately after surgery (0 hours) and at up to 3 timepoints thereafter up to 72 hours or discharge, whichever is earliest;
to 3: PUPs: Approximately 30 minutes after infusion.
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E.5.2 | Secondary end point(s) |
1. Comparison of annualized bleeding rate between different prophylaxis treatment intervals;
2. Comparison of annualized bleeding rate between 2 different prophylaxis treatment intervals and on-demand treatment;
3. rIX-FP consumed per month per subject during routine prophylaxis treatment;
4. Surgery substudy: The frequency of AEs related to rIX-FP;
5. Surgery substudy: Total number of subjects who develop inhibitors against FIX;
6. Surgery substudy: Total number of subjects who develop antibodies against rIX-FP;
7. Surgery substudy: Predicted and intraoperative estimated blood loss;
8. Surgery substudy: Predicted and actual transfusion requirements;
9. Surgery substudy: Change in hemoglobin levels between baseline, intraoperatively and postoperatively (major surgery only);
10.Overall adverse events (AEs) and rIX-FP-related AEs;
11. Hemostatic response to rIX-FP treatment in PUPs.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
to 1,2 and 3: Approximately 5 years;
to 4, 5 and 6: 28 days after surgery (major surgery) or up to hospital discharge (minor surgery);
to 7: Predicted blood loss and intraoperative estimated blood loss to be determined before surgery and at the end of surgery, respectively;
to 8: Predicted and actual transfusion requirements to be determined before and at the end of surgery, respectively;
to 9: Before, during and up to 28 days after surgery;
to 10: Approximately 5 years;
to 11: Hemostatic response of rIX-FP treatment during the course of the study (up to 5 years). |
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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 | 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 | 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.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 24 |
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 |
Austria |
Bulgaria |
Czech Republic |
France |
Germany |
Israel |
Italy |
Japan |
Malaysia |
Philippines |
South Africa |
Spain |
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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The end of the trial is defined as the last-patient-last-visit. |
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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 | |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
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 |