E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Severe hemophilia A (FVIII<1%) |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060612 |
E.1.2 | Term | Hemophilia A |
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 is to evaluate the peri-operative hemostatic efficacy of BAX855 in male PTPs aged 2-75 years with severe hemophilia A (FVIII <1%) undergoing major or minor, elective or minor emergency surgical, dental or other invasive procedures. |
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E.2.2 | Secondary objectives of the trial |
To determine the safety of BAX855 used in the perioperative setting
o The occurrence of all AEs
o The occurrence of thrombotic events and/or allergic reactions to BAX855
o To determine the development of FVIII inhibitors and binding antibodies to FVIII, BAX855 and PEG, as well as antibodies to Chinese Hamster Ovary (CHO) proteins.
• To determine the intra-and postoperative blood loss at the end of surgery and until drain removal, if applicable, compared to the estimated volume of expected average and maximum blood loss in a comparable healthy individual as predicted preoperatively by the investigator/surgeon
To determine the volume of blood, red blood cells, platelets, and other blood products transfused
• To determine the daily and total weight-adjusted consumption of BAX855 per subject |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subject requires an elective major or minor surgical, dental or other invasive procedure (e.g. biopsy, endoscopy).
2. Subject and/or legal representative has/have provided signed informed consent.
3. Subject is 2 to 75 years of age at the time of enrollment.
4. Subject is male with severe hemophilia A (FVIII level <1%) as confirmed by the central lab at screening or a documented FVIII activity level <1%.
5. Subject was previously treated with FVIII concentrates with ≥150 documented exposure days (EDs).
6. Subject is currently receiving prophylaxis or on-demand therapy with FVIII concentrate.
7. Subject has a Karnofsky performance score of ≥60 at screening.
8. Subject is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and CD4+ count ≥200 cells/mm3, as confirmed by central laboratory at screening.
9. Subject is Hepatitis C virus negative (HCV-) by antibody or PCR testing, as confirmed by central laboratory at screening; or HCV+ with chronic stable hepatitis as assessed by the investigator. If positive, antibody titer will be confirmed by PCR.
10. Subject is willing and able to comply with the requirements of the study protocol.
11. For subjects transitioning from parent BAX855 studies, the subjects continues to meet the entry criteria. |
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E.4 | Principal exclusion criteria |
1. Subject has detectable FVIII inhibitory antibodies (≥0.4 BU using the Nijmegen modification of the Bethesda assay) at screening as determined by the central laboratory or at any timepoint prior to screening (≥0.4 BU using the Nijmegen modification of the Bethesda assay or ≥0.6 BU using the Bethesda assay).
2. History of ongoing or recent thrombotic disease, fibrinolysis or disseminated intravascular coagulation (DIC).
3. Subject has a platelet count <100 x 109/L, as confirmed by central laboratory at screening.
4. Subject has severe renal impairment (serum creatinine > 2.0 mg/dL), as confirmed by central laboratory at screening.
5. Subject has severe chronic hepatic dysfunction (eg ≥5 X upper limit of normal alanine aminotransferase (ALT), as confirmed by central laboratory at screening, or a documented INR > 1.5).
6. Subject has a known hypersensitivity towards mouse or hamster proteins, polysorbate 80 or to PEG.
7. Subject is currently using or has recently (< 30 days) used pegylated drugs (other than BAX855) prior to study participation or is scheduled to use such drugs during trial participation.
8. Subject is currently participating in another clinical drug (other than BAX855) or device study or use of another investigational product or device within 30 days prior to study entry.
9. Subject has a diagnosis of an inherited or acquired hemostatic defect other than hemophilia A.
10. Subject is currently receiving, or scheduled to receive during the course of the study, an immunomodulating drug (e.g., systemic corticosteroid agent at a dose equivalent to hydrocortisone greater than 10 mg/day, or alpha interferon) other than anti-retroviral chemotherapy.
11. 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 safety or compliance.
12. The subject has an incremental recovery <1.5 IU/dL:IU/kg as determined in the parent study, if applicable.
13. Subjects undergoing minor or major emergency surgery. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Global Hemostatic Efficacy score, which is composed of 3 individual ratings:
1. Assessment of intra-operative hemostatic efficacy of BAX855 performed by the operating surgeon
2. Assessment of postoperative hemostatic efficacy of BAX855 at postoperative day 1 performed by the investigator
3. Assessment of postoperative hemostatic efficacy of BAX855 at EOS visit performed by the investigator (day 14 or discharge, whichever is first) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
6 months (±2 weeks) for first and secondary endpoints |
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E.5.2 | Secondary end point(s) |
SAFETY
• Development of neutralizing FVIII inhibitors
• Development of binding antibodies to FVIII, BAX855, and PEG
• Development of anti-CHO antibodies.
• Occurrence of thrombotic events
• Other IP-related adverse events (AEs)
• Clinically significant changes in vital signs and routine laboratory parameters (hematology, clinical chemistry and virology)
Pharmacokinetics of BAX855
Primary PK:IR and T1/2. Secondary PK: AUC0-∞/dose (area under the plasma concentration /time curve from time 0 to infinity), MRT, CL, Vss, AUC0-96h/dose (area under the plasma concentration/time curve from time 0 to 96 hours post-infusion.
Blood loss
The observed versus predicted operative blood loss will be described for the period from initiation of the intervention to 24 hours after completion of the intervention or drain removal, as applicable,
The intraoperative blood loss will be measured by determining the volume of blood and fluid removal through suction into the collection container (waste box and/or cell saver) and the estimated blood loss into swabs and towels during the procedure, per the anesthesiologist’s record. Post-operatively, blood loss will be determined by the drainage volume collected, which will likely consist mainly of drainage fluid via vacuum or gravity drain, as applicable.
Transfusion requirements
The type and number of units and amount (in mL) of blood products will be recorded. Furthermore, also salvage of blood obtained from autologous transfusion systems, e.g. cell savers, will be recorded. In addition, the type and amount of fluid replacement and volume expanders will be recorded as concomitant medication (e.g. amount and number of units of salvaged blood, red blood cells, platelets and other blood products transfused).
Bleeding Episodes
Any clinically relevant bleeding episodes, as well as the need for any further surgical interventions, are to be recorded. Study subjects will be closely monitored for the occurrence of bleeding episodes during the entire intra- and post-operative period, until the time of discharge from the investigative site or treatment facility.
Drug consumption
Daily and total weight-adjusted dose of BAX855 per subject. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
6 months (±2 weeks) for first and secondary endpoints |
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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 | Yes |
E.8.1.7.1 | Other trial design description |
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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
| 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 | 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 |
Belgium |
Bulgaria |
Lithuania |
Netherlands |
Poland |
Russian Federation |
Spain |
Ukraine |
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 | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 3 |