E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects with severe or moderately severe hemophilia A (residual factor VIII activity ≤2%) undergoing unilateral primary total knee replacement |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060612 |
E.1.2 | Term | Hemophilia A |
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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 objectives of this study are to compare the haemostatic efficacy and safety of continuous infusion (CI) versus intermittent bolus infusion (BI) in the peri – and postoperative setting employing rAHF – PFM in previously treated subjects with severe or moderately severe hemophilia A (baseline factor VIII levels ≤ 2% of normal) undergoing unilateral primary total knee replacement. |
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E.2.2 | Secondary objectives of the trial |
1. To assess and compare the cumulative PBRC volume in the drainage fluid 2. To assess and compare the total amount of hemoglobin in the drainage fluid 3. To determine the blood loss compared with the predicted blood loss 4. To determine the number of bleeding episodes during treatment with CI or BI 5. To record the occurrence and dimensions of any clinically relevant postoperative hematomas 6. To assess the number of units of PRBCs transfused 7. To assess and compare the global hemostatic efficacy between subjects receiving CI versus BI. 8. To determine the total weight-adjusted dose of rAHF PFM per subject through postoperative day 7 9. To calculate the total daily intra- and post-operative weight-adjusted dose of rAHF PFM during administration of CI or BI 10. To record the number of adverse experiences related to the administration of the study product 11. To identify the incidence of factor VIII antibody formation |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. The subject or the subject’s legally authorized representative has provided signed informed consent. 2. The subject is within 18 to 65 years of age. 3. The subject has severe or moderately severe hemophilia A, defined by a baseline factor VIII level ≤ 2% of normal, as tested at screening. A subset of 15 subjects per group must have baseline factor VIII levels <1% of normal. 4. The subject is scheduled to undergo an elective unilateral primary total knee replacement (with cemented or uncemented prosthesis). 5. The subject was previously treated with factor VIII concentrate(s) for a minimum of at least 150 exposure days (as estimated by the investigator) prior to study entry. 6. Human immunodeficiency virus (HIV) positive subjects must be immunocompetent as determined with a CD4 count ≥ 400 cells/mm³ (CD4 count at screening). 7. The subject has a life expectancy of at least 28 days from the day of surgery. |
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E.4 | Principal exclusion criteria |
1. The subject has a detectable factor VIII inhibitor at screening, with a titer ≥ 0.4 BU (Nijmegen modification of the Bethesda Assay) in the central laboratory. 2. The subject has a history of factor VIII inhibitors with a titer ³ 0.4 BU (by Bethesda or Nijmegen assay) at any time prior to screening. 3. The subject is scheduled to undergo any other concurrent minor or major surgery during the course of the study. The placement of central venous lines is permitted. 4. The subject has an abnormal renal function (serum creatinine > 1.5 mg/dL). 5. The subject has active hepatic disease (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] levels > 5 times the upper limit of normal). 6. The 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. 7. The subject has clinical and/or laboratory evidence of abnormal hemostasis from causes other than hemophilia A (e.g., late-stage chronic liver disease, immune thrombocytopenia purpura). 8. The subject is currently receiving, or is scheduled to receive during the course of the study, an immunomodulating drug other than anti-retroviral chemotherapy (e.g., a-interferon, corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day). 9. The subject has a known hypersensitivity to mouse or hamster proteins. 10. The subject is participating in another investigational drug study within 30 days prior to screening. 11. The subject is identified by the investigator as being unable or unwilling to cooperate with study procedures. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint, cumulative PRBC volume in drainage fluid during the first postoperative 24 hours, will be used to establish non-inferiority of CI to BI. A one-sided t-test at the 2.5% level of statistical significance on the log transformed data will test the null hypothesis that the mean PRBC volume with CI is 200% of the mean with BI against the alternative hypothesis that it is less. This is equivalent to the upper confidence limit of a 95% two-sided confidence interval for the ratio of means not exceeding 200%. |
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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 | 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 | Information not present in EudraCT |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
Intermittant bolus infusion |
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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.8.5 | The trial involves multiple Member States | Yes |
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 | Information not present in EudraCT |
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 |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |
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 | 10 |