E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients suffering from severe to moderately severe Haemophilia A (basal level of factor VIII < 2% of normal) undergoing Primary Total Unilateral Substitution of the Knee. |
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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 | 10061992 |
E.1.2 | Term | Haemophilia |
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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 compare the hemostatic efficacy and safety of continuous infusion (CI)to intermittent bolus infusion (BI) in the intra- and postoperative environment using rAHF-PFM in previously treated patients (PTPs) suffering from severe to moderately severe haemophilia A (basal level of factor VIII <2% of normal) undergoing primary total unilateral substitution of the knee. |
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E.2.2 | Secondary objectives of the trial |
(a)To assess and compare the cumulative packed PRBC volume and the total amount of hemoglobine in the drainage fluid during the first 24 hours following surgery (and until time of drain removal for the hemoglobine) between subjects receiving CI versus BI,(b)to determine the blood loss compared with the predicted blood loss during the first 24 hours following surgery and until removal drain, (c) to determine the number of bleeding episodes during treatment with CI or BI, (d)To record the occurrence and dimensions of any clinically relevant postoperative hematomas, (e) To assess the number of units of PRBCs transfused, (f) to assess and compare the global hemostatic efficacy between subjects receiving CI versus BI, (g) To determine the total weight-adjusted dose of rAHF PFM per subject through postoperative day 7, (h) To calculate the total daily intra-and post-operative weight-adjusted dose of rAHF PFM during administration of CI and BI, (i) To record the number of ADR |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.The subject or subjects legally authorized representative has provided signed informed consent 2.The subject is within 18 to 70 years of age, 3. The subject is suffering from severe to moderately severe Haemophilia A (basal level of factor VIII &#8804;2% of normal) at screenig.A subgroup of 15 subjects in each group will show a basal level of factor VIII <1% of normal. 4.The aPTT must be within the range of normal after administration of F VIII concentrate, ad determined in the preoperative pharmacokinetic evaluation, or as documented in the medical history, if available. 5 The subject is scheduled to undergo an elective unilateral primary total knee replacement (with cemented or uncemented prothesis) 6. The subject has a documented history of at least 150 exposure days to factor VIII concentrates, before entering the study. 6.HIV positive subjects must be immunocompetent as determined with a CD4 count&#8805; 400 cells/mm³ (CD4 at screening), but HIV negative subjects with CD count <400 qualify, if immunocompetency is documented. 8. 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 an history of factor VIII inhibitors or a detectable factor VIII inhibitors at screening with a titer &#8805; 0,4 BU; 2.The subject has an history of factor VIII inhibitors with a titer &#8805; 0,4 BU(by Nijmegen assay)or &#8805;0,5 BU (by Bethesda assay)at any time prior to screening 3. The subject is scheduled to undergo any other current minor or major surgery during the course of the study.The placement of a central venous lines and the performance of fine needle aspiration biopsies are permitted; 4.Excluding hemophilia-related physical impairments, the subject is assigned to NYHA&#8805;III according to New York Heart Association classification. 5. The subject with an abnormal renal function (serum creatinine >1.5mg/dL), 6. an active hepatic disease( [ALT]or [AST] levels >5 times the upper limit of normal), 7. a severe chronic liver disease (as evidenced by but not limited to INR >1.4, hypoalbuminemia,portal vein hypertansion, including presence of otherwise unexplained splenomegaly and history of esophageal varices, 9.The subject is currently receiving or scheduled to receive an immunomodulating drug other than antiretroviral chemotherapy; 10.a known hypersensitivity to mouse or hampster proteins. 11.The subject has received another investigational drug within 30 days prior to the screening and /or is scheduled to recieve additional investigational drug during the course of the trial in the context of another investigational drug study. 12.The subject is identified by the investigator as being unable or unwilling to cooperate with the study procedures. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint, the cumulative volume of PRBC in the drainage fluid during the first 24 hours after surgery, will be used to establish the non-inferiority of CI compared to BI. A one-way t-test at a 2.5% level of statistical significance on the transformed logarithmic data will test the null hypothesis that the average PRBC volume with CI is 200% of the average with BI, as opposed to the alternative hypothesis, which is lower. This is equivalent to the higher confidence limit of a 95% two-way confidence interval for an average percentage 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 | 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 |
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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 | 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 |
stesso farmaco con differente modalita` di dosaggio |
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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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
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 | No |
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 |