Recombinant vWF Concentrate for Bleeding
Recruiting in Palo Alto (17 mi)
Overseen byMichael Mazzeffi, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: University of Virginia
Must not be taking: Anticoagulants
Disqualifiers: Thrombophilia, DVT, Liver failure, others
No Placebo Group
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?Adult patients on extracoporeal membrane oxygenation (ECMO) frequently experience bleeding, which is in part caused by acquired von Willebrand syndrome (vWS). Prior in vitro studies have shown that the addition of recombinant von Willebrand Factor (vWF) to ECMO patient blood samples, normalizes platelet adhesion and thrombus formation. This study is a phase I study, where adult ECMO patients with refractory bleeding will be treated with recombinant vWF a single time. The primary objectives are to evaluate the safety, tolerability, and pharmacokinetics of recombinant vWF in adult ECMO patients.
Will I have to stop taking my current medications?
The trial requires that participants stop taking systemic anticoagulation medications for at least 4 hours before joining. Other medications are not specifically mentioned, so it's best to discuss with the trial team.
What data supports the effectiveness of the drug Recombinant von Willebrand Factor (rVWF) for bleeding?
Research shows that rVWF is effective in treating and preventing bleeding episodes in patients with von Willebrand disease, including during surgery. In a study, patients using rVWF had excellent or good control of bleeding, and it was well-tolerated with no severe allergic reactions reported.
12345Is Recombinant von Willebrand Factor (rVWF) safe for humans?
Recombinant von Willebrand Factor (rVWF) has been shown to be generally safe in humans, with studies reporting it was well-tolerated in patients with von Willebrand disease undergoing surgery. Some patients experienced treatment-emergent adverse events, but serious allergic reactions or inhibitory antibodies were not reported.
13467How is the drug Recombinant von Willebrand Factor (rVWF) unique compared to other treatments for bleeding in von Willebrand disease?
Recombinant von Willebrand Factor (rVWF) is unique because it is a purified concentrate produced without exposure to the VWF-cleaving enzyme ADAMTS13, preventing degradation of large VWF multimers, and it does not contain factor VIII, unlike plasma-derived products. This makes it effective for patients who need treatment without the risk of factor VIII accumulation.
128910Eligibility Criteria
This trial is for adults on ECMO with major bleeding who aren't on blood thinners for at least 4 hours. It's not for those with recent serious clots, vWF antibodies, low platelets or fibrinogen levels, high INR, liver failure, current trial participation, heparin allergy, inability to consent or pregnancy.Inclusion Criteria
You are currently using a special machine to help your heart and lungs work.
You have had severe bleeding classified as grade 3 or higher according to CTCAE.
I am 18 years old or older.
+1 more
Exclusion Criteria
Your blood's clotting ability is too high.
Your fibrinogen levels are lower than 150 mg/dL.
Current participation in another clinical trial (interventional)
+10 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
1-2 weeks
Treatment
ECMO patients with major bleeding receive a single intravenous dose of recombinant von Willebrand Factor
1 day
1 visit (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment, including pharmacokinetic assessments and adverse event monitoring
30 days
Multiple visits (in-person and virtual)
Participant Groups
The study tests a single dose of recombinant von Willebrand Factor (vWF) in adult ECMO patients with severe bleeding. The goal is to see if it's safe and how the body processes it. This phase I study aims to improve clotting by normalizing platelet adhesion.
1Treatment groups
Experimental Treatment
Group I: Treatment with recombinant vWFExperimental Treatment1 Intervention
ECMO patients with major bleeding who are enrolled in the trial will receive treatment with recombinant von Willebrand Factor a single time. The dose will be 50 IU/kg and the drug will be given intravenously.
Recombinant vWF Concentrate is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Vonvendi for:
- Bleeding episodes in adults with von Willebrand disease
🇪🇺 Approved in European Union as Veyvondi for:
- Bleeding episodes in adults with von Willebrand disease
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
UVA HospitalCharlottesville, VA
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Who Is Running the Clinical Trial?
University of VirginiaLead Sponsor
References
Pharmacokinetic-Pharmacodynamic Comparison of Recombinant and Plasma-Derived von Willebrand Factor in Patients with von Willebrand Disease Type 3. [2023]Recombinant von Willebrand factor (rVWF, vonicog alfa, Vonvendi/Veyvondi, Takeda Pharmaceuticals USA, Lexington, MA) and several plasma-derived VWF/factor VIII (pdVWF/FVIII) concentrates are available for treating bleeding episodes in patients with von Willebrand disease (VWD).
Recombinant von Willebrand factor for severe gastrointestinal bleeding unresponsive to other treatments in a patient with type 2A von Willebrand disease: a case report. [2018]: A recombinant von Willebrand factor (rVWF) was recently approved in the United States for on-demand treatment and control of bleeding episodes in adults with von Willebrand disease (VWD). In contrast to plasma-derived VWF products available in the United States, rVWF does not contain factor VIII (FVIII). To date, there is no published experience of rVWF in clinical practice. We report the acute and prophylactic use of rVWF in a patient with VWD type 2A and severe gastrointestinal bleeding. Dosing with plasma-derived VWF/FVIII concentrates was constrained by FVIII accumulation; the bleeding was unresponsive, and multiple red blood cell transfusions were required. After initiation of rVWF (4200 IU every other day), bleeding symptoms subsided, and no red blood cell transfusions were required during more than 3 months of prophylactic therapy (most recent dosage: 2800 IU every other day). rVWF may be effective in the prevention, as well as treatment, of severe bleeding symptoms in VWD.
Phase 3 study of recombinant von Willebrand factor in patients with severe von Willebrand disease who are undergoing elective surgery. [2023]Essentials Recombinant von Willebrand factor (rVWF) is effective in von Willebrand disease (VWD). A phase 3 study of rVWF, with/without recombinant factor VIII (rFVIII) before surgery in VWD. Overall rVWF's efficacy was rated excellent/good; rVWF was administered alone in most patients. rVWF was well-tolerated and hemostasis was achieved in patients with severe VWD undergoing surgery. SUMMARY: Background Recombinant von Willebrand factor (rVWF) has demonstrated efficacy for on-demand treatment of bleeding in severe von Willebrand disease (VWD), warranting evaluation in the surgical setting. Objectives This study (NCT02283268) evaluated the hemostatic efficacy/safety profile of rVWF, with/without recombinant factor VIII (rFVIII), in patients with severe VWD undergoing surgery. Patients/Methods Patients received rVWF 40-60 IU kg-1 , VWF ristocetin cofactor activity was measured 12-24 h before surgery. If endogenous FVIII activity (FVIII:C) target levels were achieved 3 h before surgery, rVWF was administered alone 1 h before surgery; rVWF was co-administered with rFVIII if target endogenous FVIII levels were not achieved. rVWF was infused postoperatively to maintain target trough levels. Overall and intraoperative hemostatic efficacy, the pharmacodynamics of rVWF administration and the incidence of adverse events (AEs) were assessed. Results All patients treated with rVWF for major (n = 10), minor (n = 4) and oral (n = 1) surgery had overall and intraoperative hemostatic efficacy ratings of excellent (73.3% and 86.7%) or good (26.7% and 13.3%). Most rVWF infusions (89.4%) were administered alone, resulting in hemostatically effective levels of endogenous FVIII within 6 h, which were sustained for 72-96 h; 70% (n = 7/10) of major surgeries were performed without rFVIII co-administration. Six patients reported 12 treatment-emergent AEs. Two patients each had one serious AE: diverticulitis (not treatment related) and deep vein thrombosis (sponsor-assessed as possibly treatment related). No severe allergic reactions or inhibitory antibodies were reported. Conclusions These data support the efficacy and safety profile of rVWF in patients with severe VWD undergoing elective surgery.
An evaluation of von Willebrand factor (recombinant) therapy for adult patients living with severe type 3 von Willebrand disease. [2023]Von Willebrand Factor (VWF) containing concentrates have been used for the treatment of von Willebrand Disease (VWD) for many years. Recently, however, a novel recombinant VWF (rVWF or vonicog alpha, VONVENDI [US], VEYVONDI [Europe]) has arrived to the market for the treatment of VWD. Initially, rVWF was approved by the U.S. Food and Drug Administration (FDA) for the on-demand treatment and control of bleeding episodes and for the perioperative management of bleeding for patients with VWD. More recently, however, the FDA has approved rVWF for routine prophylaxis to prevent bleeding episodes for those patients with severe type 3 VWD receiving on-demand therapy.
Treatment of severe von Willebrand disease with a high-purity von Willebrand factor concentrate (Wilfactin): a prospective study of 50 patients. [2023]A plasma-derived von Willebrand factor (VWF) concentrate with low factor VIII (FVIII) content was specifically developed to treat von Willebrand disease (VWD). Efficacy and safety were investigated by merging the results of two comparable protocols conducted prospectively in 5 European and 12 French centers.
Prophylaxis with recombinant von Willebrand factor in patients with type 3 von Willebrand disease: Results of a post hoc analysis from a phase 3 trial. [2023]To describe efficacy/safety of recombinant von Willebrand factor (rVWF) prophylaxis in patients with type 3 von Willebrand disease (VWD).
Outcomes in Patients With von Willebrand Disease Receiving Recombinant von Willebrand Factor on Demand and in Surgical Settings: Chart Review. [2023]This European observational chart review assessed the efficacy/safety of recombinant von Willebrand factor (rVWF) for on-demand treatment of spontaneous/traumatic bleeds and prevention and/or treatment of surgery-related bleeding in adults with von Willebrand disease (VWD). Patients (n = 91) were enrolled at first rVWF administration (index). Data were collected for the 12 months before index and until death, loss to follow-up, or end of study (3-12 months after index). Fifteen patients reported an rVWF-treated spontaneous/traumatic bleed at index. Bleed resolution was obtained for 14 patients (unknown status, n = 1), and investigators assessed treatment satisfaction for 13 rVWF prescriptions (2 moderate, 5 good, and 6 excellent). rVWF was used to prevent/treat surgery-related bleeds at index in 76 patients. Bleed resolution was achieved in 25/58 rVWF-treated surgeries; bleed resolution was not applicable for 33 surgeries. In both groups, there were no reports of treatment-emergent adverse events after initiating rVWF, including hypersensitivity reactions, thrombotic events, and VWF inhibitor development. rVWF was shown to be effective for the on-demand treatment of spontaneous/traumatic bleeds, and for the prevention and treatment of surgical bleeds in this real-world VWD population.
Structure and Function of Recombinant versus Plasma-Derived von Willebrand Factor and Impact on Multimer Pharmacokinetics in von Willebrand Disease. [2022]Recombinant von Willebrand factor (rVWF, vonicog alfa) is a purified VWF concentrate produced from Chinese hamster ovary cells. rVWF is not exposed to the VWF-cleaving protease ADAMTS13 and so is not subject to proteolytic degradation of large (L) and ultra-large (UL) VWF multimers by that enzyme.
Chromatographic preparation of a therapeutic highly purified von Willebrand factor concentrate from human cryoprecipitate. [2019]A therapeutic highly purified von Willebrand factor (vWF) concentrate has been prepared from cryoprecipitate by a three-step chromatographic procedure. After solvent/detergent treatment to inactivate viruses, the cryoprecipitate solution was chromatographed on DEAE-fractogel TSK 650 M to separate vWF from most cryoprecipitate proteins, including factor VIII (FVIII) and fibrinogen. A second DEAE-fractogel TSK 650 M was then performed to further purify vWF and to allow concentrating it to over 100 U ristocetin cofactor activity/ml. The last step on immobilized gelatin removed fibronectin and increased the purity of vWF. vWF was recovered with about 18 and 40% yield in antigen and collagen-binding (CB) activity, respectively, from cryoprecipitate. vWF was obtained in an essentially pure state corresponding to a purification factor of over 10,000-fold from plasma. Immunonephelometric and SDS-PAGE analyses of the concentrate did not reveal any detectable cryoprotein contaminants, especially fibrinogen, fibronectin, immunoglobulins and albumin. The content in intermediate- and high-molecular-weight multimers in the concentrate was similar or higher than that of plasma, as the ion-exchanger selectively favored the binding and concentration of the larger multimeric forms while reducing the amount of the smaller forms with abnormal structure and low activity. Other characteristics of the concentrate included a CB activity to antigen ratio of 1.69 and a high capacity (86%) to correct platelet adhesion in a perfusion system. Clinical use of this standardized vWF concentrate has been shown to be efficacious in the treatment of vWF patients.
Availability of clotting factor concentrates in genetically engineered form. [2019]Recombinant clotting factor concentrates provide new opportunities for the treatment of hemostatic disorders such as haemophilia A and B and von Willebrand disease. This article briefly reviews the clinical results of currently available products, the development of concentrates of clotting factor IX and von Willebrand factor and the outlook of second generation products (e.g., deletion mutants) and gene therapy of haemophilia. Further elucidation of the structure/function relationship of plasma proteins will probably lead to a new category of medicinal products for the treatment of bleeding and thrombotic diseases.