Severe Hemophilia A
Conditions
Brief summary
Recombinant factor VIII for the prevention of bleeding in patients with severe haemophilia A undergoing major surgery while receiving emicizumab prophylaxis
Detailed description
Patients with severe haemophilia A receiving emicizumab will often need concomitant FVIII to provide haemostatic cover during major surgery. This prospective, open-label, uncontrolled, single-arm, multinational, multicentre study aims to evaluate the overall perioperative haemostatic efficacy of Nuwiq, a recombinant factor VIII, in combination with emicizumab prophylaxis in male patients over 12 with severe haemophilia A undergoing major surgery.
Interventions
DRUGNuwiq
Nuwiq is a purified B-domain-deleted FVIII glycoprotein synthesised by a genetically engineered human embryonic kidney cell line (HEK 293F).
Sponsors
Octapharma
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Severe haemophilia A (FVIII activity \[FVIII:C\] \<1%) according to medical history * Male patients at least 12 years of age * Previous treatment with any FVIII product(s) for at least 150 exposure days * On regular prophylaxis with emicizumab for at least 1 month prior to a scheduled major elective surgery requiring FVIII treatment * Freely given written informed consent of the patient, or parent/legal representative where applicable, obtained in accordance with local regulations
Exclusion criteria
* Coagulation disorder other than haemophilia A * Present or past FVIII inhibitor (≥0.6 Bethesda units \[BU\]/mL) according to medical history * Severe liver or kidney disease (alanine aminotransferase \[ALT\] and/or aspartate aminotransferase \[AST\] levels \>5 times the upper limit of normal; or creatinine \>120 μmol/L) * Known hypersensitivity to Nuwiq's active substance or its excipients (sucrose, sodium chloride, calcium chloride dihydrate, arginine hydrochloride, sodium citrate dihydrate, poloxamer 188) * Already had surgery in this study * Current participation in another interventional clinical trial * Treatment with any investigational medicinal product (IMP) within 30 days prior to screening visit
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall haemostatic efficacy | During surgery and until completion of wound healing (e.g. removal of sutures, cessation of drainage, etc.) as defined by the investigator, during the study duration of 30 ± 3 days after the day of surgical procedure | Overall haemostatic efficacy of treatment measured as binary "success" or "failure". The overall perioperative haemostatic efficacy of Nuwiq will be adjudicated by an Independent Data Monitoring Committee (IDMC) and determined using a composite assessment algorithm that considers the surgeon's assessment of intraoperative haemostatic efficacy and the investigator's assessment of postoperative haemostatic efficacy to classify the overall haemostatic efficacy as success or failure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Intraoperative haemostatic efficacy | During surgery: From first skin incision to last suture | Assessment of intraoperative haemostatic efficacy of Nuwiq using a 4-point ordinal scale: Excellent: Intraoperative blood loss was lower than or equal to the average expected blood loss for the type of procedure performed in a patient with normal haemostasis and of the same sex, age, and stature Good: Intraoperative blood loss was higher than the average expected blood loss but lower or equal to the maximal expected blood loss for the type of procedure in a patient with normal haemostasis. Moderate: Intraoperative blood loss was higher than the maximum expected blood loss for the type of procedure performed in a patient with normal haemostasis, but haemostasis was controlled. None: Haemostasis was uncontrolled, necessitating a change in the clotting factor replacement regimen. |
| Postoperative haemostatic efficacy | From end of surgery until completion of wound healing (e.g. removal of sutures, cessation of drainage, etc.) as defined by the investigator, during the study duration of 30 ± 3 days after the day of surgical procedure | Assessment of postoperative haemostatic efficacy of Nuwiq using a 4-point ordinal scale: Excellent: No postoperative bleeding or oozing that was not due to complications of surgery. All postoperative bleeding (due to complications of surgery) was controlled with Nuwiq as anticipated for the type of procedure. Good: No postoperative bleeding or oozing that was not due to complications of surgery. Control of postoperative bleeding due to complications of surgery required increased dosing with Nuwiq or additional injections not originally anticipated for the type of procedure. Moderate: Some postoperative bleeding and oozing that was not due to complications of surgery. Control of postoperative bleeding required increased dosing with Nuwiq or additional injections not originally anticipated for the type of procedure. None: Extensive uncontrolled postoperative bleeding and oozing. |
| Blood product transfusion levels | From day of surgery until completion of wound healing (e.g. removal of sutures, cessation of drainage, etc.) as defined by the investigator, during the study duration of 30 ± 3 days after the day of surgical procedure | The number of allogeneic blood products (red blood cells, platelets, and other blood products) transfused |
| FVIII plasma levels | ≤30 minutes before and 15-30 minutes after Nuwiq injection | Perioperative plasma levels |
| Thrombin generation | ≤30 minutes before and 15-30 minutes after Nuwiq injection | Perioperative thrombin generation |
| Perioperative haemostatic efficacy per World Federation of Hemophilia (WFH) criteria | Perioperative | Assessed on WFH recommended 4-point scale: Excellent: Intra and post-operative blood loss, with blood component transfusions, similar to non-haemophilic patients. No additional FVIII/bypassing agents Good: Intra/ post-operative blood loss slightly increased over expectation for non-haemophilic patient but clinically insignificant. Blood component transfusions similar to non-haemophilic patient. No additional FVIII/bypassing agents Fair: Intra/ post-operative blood loss increased over expectation for non-haemophilic patients, and additional treatment needed. Extra dose of FVIII/bypassing agents needed or increased blood component of anticipated transfusion requirement Poor: Significant intra- or post-operative blood loss substantially increased over non-haemophilic patient, requires haemophilia-related medical intervention. Unexpected hypotension, transfer to ICU due to bleeding or substantially increased blood component of anticipated transfusion requirement |
| Thrombotic events | From start of first Nuwiq injection to 30 ± 3 days following the surgical procedure or until day of discharge, whichever is later | Incidence of thrombotic events during the study |
| FVIII inhibitor formation | From start of first Nuwiq injection to 30 ± 3 days following the surgical procedure or until day of discharge, whichever is later | Incidence of FVIII inhibitor formation |
| Adverse events | From start of first Nuwiq injection to 30 ± 3 days following the surgical procedure or until day of discharge, whichever is later | Incidence of adverse events recorded during the full study period |
Countries
Croatia, Finland, France, Germany, India, Italy, North Macedonia, Serbia, Spain, United Kingdom, United States
Contacts
CONTACTSigurd Knaub, PhD
PRINCIPAL_INVESTIGATORShveta Gupta, MD
Arnold Palmer Hospital for Children
Outcome results
None listed