Recombinant vWF Concentrate for Bleeding

Overseen By Keita Ikeda, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Virginia

Must not be taking: Anticoagulants

Disqualifiers: Thrombophilia, DVT, Liver failure, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1 day

20 Participants Needed

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. ^{1 2 3 4 5}

Is 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. ^{1 3 4 6 7}

How 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. ^{1 2 8 9 10}

Research Team

Michael Mazzeffi, MD

Principal Investigator

UVA

Eligibility 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.

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)

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)

Treatment Details

Interventions

• Recombinant vWF Concentrate

Trial Overview 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.

Participant Groups

Group I: Treatment with recombinant vWF Experimental Treatment 1 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

Who Is Running the Clinical Trial?

University of Virginia

Lead Sponsor

Trials

802

Recruited

1,342,000+

Findings from Research

Recombinant von Willebrand factor (rVWF) has a significantly longer mean residence time and half-life compared to plasma-derived VWF/factor VIII (pdVWF/FVIII) in patients with von Willebrand disease, indicating a prolonged therapeutic effect.

Simulations suggest that administering rVWF can maintain FVIII activity levels above 40 IU/dL for the entire 72-hour dosing interval, making it a potentially more effective treatment option for managing bleeding episodes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic-Pharmacodynamic Comparison of Recombinant and Plasma-Derived von Willebrand Factor in Patients with von Willebrand Disease Type 3. Bauer, A., Friberg-Hietala, S., Smania, G., et al.[2023]

A recombinant von Willebrand factor (rVWF) was successfully used in a patient with von Willebrand disease type 2A to control severe gastrointestinal bleeding, demonstrating its efficacy in acute treatment.

After starting rVWF therapy, the patient experienced a significant reduction in bleeding symptoms and did not require any red blood cell transfusions for over 3 months, indicating its potential for both treatment and prophylaxis in managing bleeding episodes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recombinant von Willebrand factor for severe gastrointestinal bleeding unresponsive to other treatments in a patient with type 2A von Willebrand disease: a case report. Brown, R.[2018]

In a phase 3 study involving patients with severe von Willebrand disease (VWD) undergoing surgery, recombinant von Willebrand factor (rVWF) demonstrated excellent or good hemostatic efficacy in 100% of cases, with 73.3% rated as excellent overall.

rVWF was well-tolerated, with most patients (89.4%) receiving it alone, achieving effective levels of endogenous factor VIII for up to 96 hours, and no severe allergic reactions were reported, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 3 study of recombinant von Willebrand factor in patients with severe von Willebrand disease who are undergoing elective surgery. Peyvandi, F., Mamaev, A., Wang, JD., et al.[2023]

The novel recombinant von Willebrand Factor (rVWF) has been FDA approved for routine prophylaxis to prevent bleeding episodes in patients with severe type 3 von Willebrand Disease (VWD), expanding its use beyond on-demand treatment.

Phase III trial results suggest that rVWF may have superior hemostatic potential compared to traditional plasma-derived VWF concentrates, likely due to its unique structure that includes ultra-large VWF multimers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An evaluation of von Willebrand factor (recombinant) therapy for adult patients living with severe type 3 von Willebrand disease. Hancock, JM., Escobar, MA.[2023]

A plasma-derived von Willebrand factor concentrate was shown to be effective in treating severe von Willebrand disease, with 89% of treated bleeding episodes resulting in excellent or good outcomes.

The treatment was safe, with no thrombotic complications reported and no development of antibodies against VWF or FVIII in patients, indicating a favorable safety profile for this concentrate.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of severe von Willebrand disease with a high-purity von Willebrand factor concentrate (Wilfactin): a prospective study of 50 patients. Borel-Derlon, A., Federici, AB., Roussel-Robert, V., et al.[2023]

In a post hoc analysis of a phase 3 trial involving 18 adults with type 3 von Willebrand disease, recombinant von Willebrand factor (rVWF) prophylaxis significantly reduced annualized bleeding rates by 91.6% in patients previously treated on-demand, indicating its high efficacy.

The safety profile of rVWF was favorable, with only one non-serious adverse event reported and no serious treatment-related adverse events or development of von Willebrand factor inhibitors, suggesting it is a safe option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Leebeek, FWG., Peyvandi, F., Tiede, A., et al.[2023]

In a study involving 91 adults with von Willebrand disease, recombinant von Willebrand factor (rVWF) effectively treated spontaneous and traumatic bleeds, achieving resolution in 14 out of 15 cases.

rVWF was also effective in preventing and treating surgery-related bleeds, with a resolution rate of 25 out of 58 surgeries, and no treatment-emergent adverse events were reported, indicating a strong safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes in Patients With von Willebrand Disease Receiving Recombinant von Willebrand Factor on Demand and in Surgical Settings: Chart Review. Sun, SX., Lowndes, S., Willock, R., et al.[2023]

Recombinant von Willebrand factor (rVWF) maintains a non-degraded multimeric structure, including large (L) and ultra-large (UL) VWF multimers, which are absent in human plasma-derived VWF concentrates, potentially enhancing its hemostatic efficacy.

rVWF exhibits superior platelet-binding activity and faster platelet adhesion under shear stress compared to plasma-derived VWF concentrates, indicating its effectiveness in treating patients with severe von Willebrand disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Structure and Function of Recombinant versus Plasma-Derived von Willebrand Factor and Impact on Multimer Pharmacokinetics in von Willebrand Disease. Gritsch, H., Schrenk, G., Weinhappl, N., et al.[2022]

A highly purified von Willebrand factor (vWF) concentrate was developed using a three-step chromatographic process, achieving over 10,000-fold purification from plasma and ensuring no detectable contaminants like fibrinogen or immunoglobulins.

The concentrate demonstrated a high capacity to correct platelet adhesion and has been clinically shown to be effective in treating patients with von Willebrand disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chromatographic preparation of a therapeutic highly purified von Willebrand factor concentrate from human cryoprecipitate. Burnouf-Radosevich, M., Burnouf, T.[2019]

Recombinant clotting factor concentrates are effective treatments for hemostatic disorders like hemophilia A and B, as well as von Willebrand disease, offering new therapeutic options.

Ongoing research into the structure and function of plasma proteins may lead to innovative treatments, including second-generation clotting factors and gene therapy for hemophilia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Availability of clotting factor concentrates in genetically engineered form. van Aken, WG.[2019]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Pharmacokinetic-Pharmacodynamic Comparison of Recombinant and Plasma-Derived von Willebrand Factor in Patients with von Willebrand Disease Type 3. [2023]

2. England pubmed.ncbi.nlm.nih.gov

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]

3. England pubmed.ncbi.nlm.nih.gov

Phase 3 study of recombinant von Willebrand factor in patients with severe von Willebrand disease who are undergoing elective surgery. [2023]

4. England pubmed.ncbi.nlm.nih.gov

An evaluation of von Willebrand factor (recombinant) therapy for adult patients living with severe type 3 von Willebrand disease. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Treatment of severe von Willebrand disease with a high-purity von Willebrand factor concentrate (Wilfactin): a prospective study of 50 patients. [2023]

6. England pubmed.ncbi.nlm.nih.gov

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]

7. United States pubmed.ncbi.nlm.nih.gov

Outcomes in Patients With von Willebrand Disease Receiving Recombinant von Willebrand Factor on Demand and in Surgical Settings: Chart Review. [2023]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Structure and Function of Recombinant versus Plasma-Derived von Willebrand Factor and Impact on Multimer Pharmacokinetics in von Willebrand Disease. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Chromatographic preparation of a therapeutic highly purified von Willebrand factor concentrate from human cryoprecipitate. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Availability of clotting factor concentrates in genetically engineered form. [2019]