E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Subjects with Severe or Moderately Severe Hemophilia A (baseline
factor VIII (FVIII) level <= 2% of normal) hemophilia A undergoing major orthopedic surgery |
|
E.1.1.1 | Medical condition in easily understood language |
Subjects with Severe or Moderately Severe Hemophilia A (baseline
factor VIII (FVIII) level <= 2% of normal) hemophilia A undergoing major orthopedic surgery |
|
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 | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060612 |
E.1.2 | Term | Hemophilia A |
E.1.2 | System Organ Class | 100000004850 |
|
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 compare the hemostatic efficacy of CI versus intermittent BI in the peri- and post-operative setting employing rAHF PFM in PTPs with severe or moderately severe hemophilia A (baseline FVIII level ≤ 2% of normal) undergoing elective unilateral major orthopedic surgery that requires drain placement by assessing the cumulative packed red blood cell (PRBC) volume in the drainage fluid during the first 24 hours following surgery.
Secondary Objectives: Efficacy
1. To assess and compare the total amount of hemoglobin in the drainage fluid during the first 24 hours following surgery and until time of drain removal between subjects receiving CI versus BI
2. To determine the blood loss compared with the predicted blood loss during the first 24 hours following surgery, as predicted preoperatively by the operating surgeon
3. To determine the blood loss compared with the predicted blood loss until removal of drain, as predicted preoperatively by the operating surgeon |
|
E.2.2 | Secondary objectives of the trial |
4. To determine the number of bleeding episodes during treatment with CI or BI (through postoperative Day 7)
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 of rAHF-PFM using an exploratory score between subjects receiving CI versus BI. This will be achieved by determining the following parameters:
a. To assess and compare the intraoperative hemostatic efficacy of rAHFPFM between subjects receiving CI versus BI
b. To assess and compare the volume in drains between subjects receiving CI versus BI at 24 hours following surgery
c. To assess and compare hemostatic efficacy of rAHF-PFM at postoperative Day 8 for the 2 subject groups
8. To determine the total weight-adjusted dose of rAHF-PFM per subject from a loading dose to postoperative Day 7 (IU/kg body weight/subject)
to be continued - Please see protocol on page 9 |
|
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 70 years of age.
3. The subject has severe or moderately severe hemophilia A, defined by a baseline FVIII level ≤ 2% of normal, as tested at screening. A subset of 15 subjects per group must have baseline FVIII levels < 1% of normal.
4. The aPTT must be within the range of normal after administration of FVIII concentrate, as 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 major orthopedic surgery that requires drain placement.
6. The subject was previously treated with FVIII concentrate(s) for a minimum of at least 150 exposure days prior to study entry.
7. Human immunodeficiency virus (HIV) positive subjects must be immunocompetent as determined with a CD4+ count ≥ 200 cells/mm³ (CD4+ count at screening), but HIV negative subjects with a CD4+ count < 200 cells/mm³ qualify, if immunocompetency is documented.
8. The subject has a life expectancy of at least 28 days from the day of surgery. |
|
E.4 | Principal exclusion criteria |
1. The subject has a detectable FVIII 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 FVIII inhibitors with a titer ≥ 0.4BU (by Nijmegen assay) or ≥ 0.5 BU (by Bethesda 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 and the performance of fine needle aspiration biopsies are permitted.
4. Excluding hemophilia-related physical impairments, the subject is assigned to NYHA class ≥ III according to the New York Heart Association (NYHA).
5. The subject has an abnormal renal function (serum creatinine > 1.5 mg/dL).
6. The subject has active hepatic disease (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] levels > 5 times the upper limit of normal).
7. 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.
8. The subject has clinical and/or laboratory evidence of abnormal hemostasis from causes other than hemophilia A (eg, late-stage chronic liver disease, immune thrombocytopenic purpura).
9. The subject is currently receiving, or is scheduled to receive during the course of the study, an immunomodulating drug other than anti-retroviral chemotherapy (eg, α-interferon, corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day).
10.The subject has a known hypersensitivity to mouse or hamster proteins.
11.The subject has received another investigational drug within 30 days prior to screening and/or is scheduled to receive 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 study procedures. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Cumulative PRBC volume in the drainage fluid during the first 24 hours following surgery in subjects receiving rAHF-PFM by BI or CI |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
1. Efficacy
1. Actual postoperative blood loss during the first 24 hours compared with the average blood loss as predicted preoperatively by the operating surgeon
2. Actual postoperative blood loss compared to the expected average blood loss until drain removal as predicted preoperatively by the surgeon
3. Number of bleeding episodes during treatment with CI or BI through postoperative Day 7
4. Number of units of PRBCs transfused
2. Safety
1. Number of AEs related to the administration of the study product
2. Incidence of FVIII inhibitory antibody (≥0.4 BU using the Nijmegen modification of the Bethesda assay) formation.
3. Exploratory Outcome Measures:
1. Total amount of hemoglobin in the cumulative drainage fluid during the first postoperative 24 hours and until time of drain removal, if drainage continues beyond 24 hours
2. Occurrence and dimensions of any clinically relevant postoperative hematomas
3. Determination of an exploratory global hemostatic efficacy assessment score (GHEA), which is composed of 3 different categories:
a. Assessment of intra-operative hemostatic efficacy of rAHF-PFM performed by the operating surgeon
b. Assessment of blood loss in drains within the first 24 hours postoperatively performed by the operating surgeon
c. Assessment of postoperative hemostatic efficacy of rAHF-PFM at postoperative Day 8 performed by the investigator.
4. Total weight-adjusted dose of rAHF-PFM per subject through postoperative Day 7 (IU/kg body weight/subject)
5. Total daily intra- and post-operative weight-adjusted dose of rAHF-PFM (IU/kg body weight/day/subject)
6. Pharmacokinetic parameters: AUC0-48h, total AUC, AUMC, T½, CL, MRT, Vss, Cmax, and IR. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Efficacy
1. First postoperative 24 hours.
2. Until time of drains removal, if drainage continues beyond 24 hours.
3. Post-operative day 8
4. Post-operative day 8
2. Safety
1. End-of-study visit
2. End-of-study visit
3. Exploratory Outcome Measures:
1. First postoperative 24 hours and until time of drains removal, if drainage continues beyond 24 hours.
2. Post-operative day 8
3. Post-operative day 8
4. Post-operative day 7
5. End of study period
6. PK assessment
|
|
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 | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 |
|
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 |
Austria |
Belgium |
Czech Republic |
France |
Hungary |
Italy |
Netherlands |
Norway |
Poland |
Portugal |
Spain |
Sweden |
United Kingdom |
United States |
|
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
|
last visit of last subject |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 10 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 10 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |