E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Congenital Haemophilia A with Factor VIII Inhibitors |
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E.1.1.1 | Medical condition in easily understood language |
Congenital Haemophilia A with Factor VIII Inhibitors |
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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 | 10053751 |
E.1.2 | Term | Hemophilia A with anti factor VIII |
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 |
The primary objective of the study is to evaluate the perioperative hemostatic efficacy of BAX 802 in male subjects with CHA with inhibitors to hFVIII undergoing major or minor elective surgical, dental, or other invasive procedures as determined by the Global Hemostatic Efficacy Assessment (GHEA) score. |
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E.2.2 | Secondary objectives of the trial |
To determine:
1. the safety of BAX 802 used in the perioperative setting by assessing:
The development of and change titer of anti-porcine FVIII (pFVIII) and anti-hFVIII antibodies (binding and neutralizing), and development of binding antibodies to baby hamster kidney (BHK) proteins
-The ocurrence of thrombo-embolic events and/or allergic reactions to BAX 802
-The occurrence of adverse (AEs) related to BAX802
-The occurrence of clinically significant changes in vital signs and routine laboratory parameters related to BAX 802
2. To determine the intra- and postoperative and overall perioperative blood loss, compared to the estimated volume of expected average and maximum blood loss in a comparable healthy individual as predicted preoperatively by the Investigator/surgeon.
3.The determine the proportion of major surgeries with good or excellent hemostatic score
4To determine the daily and total weight-adjusted administration of BAX 802 per subject
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Subject requires a major or minor elective surgical, dental or other invasive procedure
2 Subject is male and ≥ 12 to ≤ 75 years old at the time of screening
3. Subject has provided signed informed consent (and assent for adolescent subjects, as applicable) in accordance with local regulatory requirements
4. Subject has severe (FVIII level < 1%) or moderately severe (FVIII level ≤ 2%) CHA with inhibitors to hFVIII ≥ 0.6 BU , as tested at screening at the central laboratory
5. Subject is not currently receiving or has received (< 30 days) ITI therapy
6. Subject has a Karnofsky performance score of ≥ 60 at screening
7. Subject is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and CD4+ count ≥ 200 cells/mm3 at screening
8. Subject is hepatitis C virus negative (HCV-) by antibody or polymerase chain reaction (PCR) testing; or HCV+ with chronic stable hepatitis disease. Positive serologies will be confirmed by PCR testing.
9. Subject is willing and able to comply with the requirements of the protocol. |
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E.4 | Principal exclusion criteria |
1. The subject requires emergency surgery
2.Severe chronic liver dysfunction or disease eg, ≥ 5 X upper limit of normal (ULN) alanine aminotransferase [ALT], as confirmed by central laboratory at screening, or a documented prothrombin time/international normalized ratio (PT/INR) > 1.5)
3.Clinically symptomatic renal disease (serum creatinine > 2.0 mg/dl), as confirmed by central lboaratory at screening
4. Anti-porcine inhibitor > 10 BU prior to surgery
5. Platelet count < 100,000/μL at screening
6. Subject has another active coagulation disorder other than haemophilia A, as per the medical history
7. Planned use of α-interferon with or without ribavarin for HCV infected patients or planned use of a protease inhibitor for HIV infected patients. Patients currently taking any of these medications for ≥ 30 days are eligible
8. Known hypersensitivity to rpFVIII, or hamster or murine proteins
9.Subject has an ongoing or recent (within 3 months of screening) thrombo-embolic disease, fibrinolysis or disseminated intravascualr coagulation (DIC)
10. Subject has been exposed to an IP within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study
11. Subject is unable to tolerate quantity of blood to be drawn for protocol procedures
12. Subject is a family member or employee of the investigator. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome measure is the proportion of all surgical, dental, or other invasive procedures with a "good" or "excellent"response as measured by GHEA score which is composed of 3 individual ratings:
-GHEA1: Assessment of intraoperative (Day 0) hemostatic efficacy of BAX 802 performed by the operating surgeon at the end of surgery.
-GHEA2: Assessment of postoperative hemostatic efficacy of BAX 802 at postoperative Day 1 (approximately 24 hours ( +/- 6 hours) post-surgery) performed by the operating surgeon. Note: If a patient is didischarged <24 hours following surgery, then the GHEA2 hemostatic efficacy assessment will require a return visit the following day.
-GHEA3: Assessment of overall perioperative hemostatic efficacy of BAX 802 at
the GHEA3 Visit (discharge or within 24 to 72 hours after the last perioperative treatment dose of BAX 802 (whichever is earlier), performed by the investigator , and where possible, also by the operating surgeon. Assessment by both is strongly recommended. In cases where there are differing assessment, the Investigator's assessment will be used.
The scores of each of the 3 individual ratings (GHEA1, GHEA2 and GHEA3 described above, will be added together to form a GHEA score. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Varying times as defined by the protocol. |
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E.5.2 | Secondary end point(s) |
Efficacy
1. Intra-and post operative blood loss compared to the estimated volume of expected average blood loss and expected maximum blood loss in a comparable healthy individual with similar demographic characteristics as predicted preoperatively by the investigator/surgeon at the following time points:
• Intraoperative, from start until the end of surgery
• Postoperative Day 1, from end of the surgery to approximately 24 hours ( +/-6 hours after surgery
• Overall perioperative at discharge or 24 to 72 hours after the last perioperative treatment dose of BAX 802 (whichever is earlier).
2. Proportion of major surgeries with good or excellent hemostatic score
3. Daily and total weight-adjusted administration of BAX 802 per subject
4. Amount of blood products (e.g whole blood, red blood cells, platelets and plasma transfused.
Safety
1. Development of, and changes to, the titer of inhibitory and binding antibodies (IgG and IgM) to pFVIII
2. Development of, and changes to, the titer of inhibitory and binding antibodies
(IgG and IgM) to hFVIII
3. Development of binding antibodies to BHK proteins
4. Occurrence of thrombo-embolic events
5. Incidence of severe allergic reactions (eg, anaphylaxis)
6. Incidence of other IP-related AEs
7. Incidence of clinically significant changes in vital signs and routine laboratory parameters (hematology, clinical chemistry) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Varying times as defined by the protocol. |
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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 | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
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.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
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 |
Canada |
Germany |
Italy |
Netherlands |
Norway |
Russian Federation |
South Africa |
Spain |
Turkey |
United Kingdom |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 0 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |