Pharmacokinetics, Safety and Efficacy of Recombinant Von Willebrand Factor (rVWF) in the Treatment of Bleeding Episodes in Von Willebrand Disease (VWD)

NCT01410227 | Completed Phase 3 Results DMC

• 2 other identifiers: 0710012010-024108-84
• Study Type: interventional
• Target: 49
• Locations: 15 countries
• Sites: 50

Brief Summary

The purpose of this Phase 3 study is to assess the pharmacokinetics of rVWF:rFVIII and rVWF, and to assess the safety and efficacy of rVWF:rFVIII and rVWF in the treatment of bleeding events in subjects with severe hereditary von Willebrand disease (VWD).

Conditions

Von Willebrand Disease

Outcome Measures

Primary Outcomes (1)

• Percentage of Participants With Treatment Success for Treated Bleeding Episodes

  Treatment success was defined as the extent of control of bleeding episodes (BEs) using a mean efficacy rating score of \<2.5 for a participant's BEs treated with study product (recombinant von Willebrand Factor \[rVWF\] with or without recombinant factor VIII \[rFVIII\]) during the study period. Scores used: Excellent = 1 - actual infusions ≤ estimated number of infusions required to treat BE; no additional VWF required (all BEs); Good = 2 - \>1-2 infusions (minor/moderate BEs) or \<1.5 infusions (major BEs) greater than estimated required to control BE; no additional VWF required (all BEs); Moderate = 3 ≥ 3 infusions (minor/moderate BEs) or ≥ 1.5 infusions (major BEs) greater than estimated required to control BE; no additional VWF required (all BEs); None = 4 - severe uncontrolled bleeding or intensity of bleeding not changed; additional VWF required. Included participants with available primary efficacy rating (prospective-excluding gastrointestinal bleeds) in the Full Analysis Set.

  For 12 months after first infusion of rVWF:rFVIII or rVWF

Secondary Outcomes (66)

• Percentage of Treated Bleeding Episodes With an Efficacy Rating of "Excellent" or "Good"

  For 12 months after first infusion of rVWF:rFVIII or rVWF

• Percentage of Treated Bleeding Episodes With an Efficacy Rating of "Excellent" or "Good", Excluding Gastrointestinal Bleeds

  For 12 months after first infusion of rVWF:rFVIII or rVWF

• Number of Infusions of rVWF:rFVIII and/or rVWF Per Bleeding Episode

  For 12 months after first infusion of rVWF:rFVIII or rVWF

• Number of Units of rVWF:rFVIII and/or rVWF Per Bleeding Episode

  For 12 months after first infusion of rVWF:rFVIII or rVWF

• Percentage of Participants Who Develop Inhibitory Antibodies to FVIII

  For 12 months after first infusion of rVWF:rFVIII or rVWF

Study Arms (4)

PK 80 Arm (minimum of 22 subjects with severe VWD)

EXPERIMENTAL

PK assessment (80 IU/kg rVWF) + 12-month treatment period

Biological: Recombinant von Willebrand factor (rVWF); Biological: Recombinant factor VIIII (rFVIII)

PK 50 Arm (14 subjects with type 3 VWD)

EXPERIMENTAL

Two single-blinded PK assessments (50 IU/kg rVWF + rFVIII/placebo) + 12-month treatment period

Biological: Recombinant von Willebrand factor (rVWF); Drug: Placebo; Biological: Recombinant factor VIIII (rFVIII)

PK 50 Only Arm (minimum of 7 subjects with type 3 VWD)

EXPERIMENTAL

PK assessment (50 IU/kg rVWF) only, no treatment of bleeding episodes

Biological: Recombinant von Willebrand factor (rVWF); Drug: Placebo; Biological: Recombinant factor VIIII (rFVIII)

Treatment Only (up to 7 subjects independent of VWD subtype)

EXPERIMENTAL

Treatment of bleeding episodes for a total of 12 months

Biological: Recombinant von Willebrand factor (rVWF); Biological: Recombinant factor VIIII (rFVIII)

Interventions

Recombinant von Willebrand factor (rVWF) BIOLOGICAL

Intravenous administration

Also known as: BAX 111, rVWF

PK 50 Arm (14 subjects with type 3 VWD); PK 50 Only Arm (minimum of 7 subjects with type 3 VWD); PK 80 Arm (minimum of 22 subjects with severe VWD); Treatment Only (up to 7 subjects independent of VWD subtype)

Placebo DRUG

Syringe supplied with physiologic saline solution for infusion

Also known as: saline, physiologic saline

PK 50 Arm (14 subjects with type 3 VWD); PK 50 Only Arm (minimum of 7 subjects with type 3 VWD)

Recombinant factor VIIII (rFVIII) BIOLOGICAL

Intravenous administration

Also known as: rFVIII, ADVATE

PK 50 Arm (14 subjects with type 3 VWD); PK 50 Only Arm (minimum of 7 subjects with type 3 VWD); PK 80 Arm (minimum of 22 subjects with severe VWD); Treatment Only (up to 7 subjects independent of VWD subtype)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participant has been diagnosed with:
• Type 1 (Von Willebrand factor: Ristocetin cofactor activity (VWF:RCo) \< 20 IU/dL) or,
• Type 2A (VWF:RCo \< 20 IU/dL), Type 2B (as diagnosed by genotype), Type 2N (Factor VIII activity (FVIII:C) \<10% and historically documented genetics), Type 2M or,
• Type 3 ( Von Willebrand factor antigen (VWF:Ag) ≤ 3 IU/dL) or,
• Severe Von Willebrand disease (VWD) with a history of requiring substitution therapy with von Willebrand factor concentrate to control bleeding
• Participant, who participates in the treatment for bleeding episodes, has had a minimum of 1 documented bleed (medical history) requiring VWF coagulation factor replacement therapy during the previous 12 months prior to enrollment.
• Participant has a Karnofsky score ≥ 60%
• Participant is at least 18 and not older than 65 years of age at enrollment
• If female of childbearing potential, participant presents with a negative pregnancy test
• Participant agrees to employ adequate birth control measures for the duration of the study
• Participant is willing and able to comply with the requirements of the protocol

You may not qualify if:

• Participant has been diagnosed with pseudo VWD or another hereditary or acquired coagulation disorder other than VWD (eg qualitative and quantitative platelet disorders or elevated PT/international normalized ratio \[INR\] \>1.4).
• Participant has a documented history of a VWF:RCo half-life of \<6 hours.
• Participant has a history or presence of a VWF inhibitor at screening.
• Participant has a history or presence of a factor VIII (FVIII) inhibitor with a titer ≥0.4 BU (by Nijmegen assay) or ≥ 0.6 BU (by Bethesda assay).
• Participant has a known hypersensitivity to any of the components of the study drugs, such as mouse or hamster proteins.
• Participant has a medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
• Participant has a medical history of a thromboembolic event.
• Participant is HIV positive with an absolute CD4 count \<200/mm3.
• Participant has been diagnosed with cardiovascular disease (New York Heart Association \[NYHA\] classes 1-4.
• Participant has an acute illness (eg, influenza, flu-like syndrome, allergic rhinitis/conjunctivitis, non-seasonal asthma) at screening.
• Participant has been diagnosed with significant liver disease as evidenced by any of the following: serum alanine aminotransferase (ALT) 5 times the upper limit of normal; hypoalbuminemia; portal vein hypertension (eg, presence of otherwise unexplained splenomegaly, history of esophageal varices).
• Participant has been diagnosed with renal disease, with a serum creatinine level ≥2 mg/dL.
• In the judgment of the investigator, the participant has another clinically significant concomitant disease (eg, uncontrolled hypertension) that may pose additional risks for the participant.
• Participant has been treated with an immunomodulatory drug, excluding topical treatment (eg, ointments, nasal sprays), within 30 days prior to enrollment
• Participant is pregnant or lactating at the time of enrollment.

Sponsors & Collaborators

• Baxalta now part of Shire: lead

Study Sites (52)

University of California Davis Cancer Center

Sacramento, California, 95817, United States

Location

University of Miami Miller School of Medicine

Miami, Florida, 33101, United States

Location

University of Illinois College of Medicine at Peoria

Peoria, Illinois, 61614, United States

Location

Indiana Hemophilia and Thrombosis Center

Indianapolis, Indiana, 46260, United States

Location

Newark Beth Israel Medical Center

Newark, New Jersey, 07112, United States

Location

The Mary M Gooley Hemophilia Center and Rochester General Hospital

Rochester, New York, 14621, United States

Location

University of North Carolina at Chapel Hill

Chapel Hill, North Carolina, 27599, United States

Location

Pennsylvania Hospital

Philadelphia, Pennsylvania, 19104, United States

Location

Hemophilia Center of Western Pennsylvania

Pittsburgh, Pennsylvania, 15213, United States

Location

Blood Center of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Royal Adelaide Hospital

Adelaide, South Australia, 5000, Australia

Location

Royal Perth Hospital

Perth, Western Australia, 6847, Australia

Location

Medical University Vienna

Vienna, 1090, Austria

Location

Cliniques Universitaires Saint-Luc

Brussels, 1200, Belgium

Location

UZ Leuven

Leuven, 3000, Belgium

Location

Specialized Haematological Hospital "Joan Pavel"

Sofia, 1233, Bulgaria

Location

Multiprofile Hospital for Active Treatment "Sveta Marina"

Varna, 9010, Bulgaria

Location

University of Alberta Hospital

Edmonton, Alberta, T6G 2H7, Canada

Location

Vivantes Klinikum im Friedrichshain

Berlin, 10249, Germany

Location

Gerinnungszentrum Rhein-Ruhr

Duisburg, 47051, Germany

Location

Universitätsmedizin der Johannes Gutenberg Universität Mainz

Mainz, 55131, Germany

Location

Jehangir Clinical Development Centre Pvt. Ltd.

Pune, 411001, India

Location

Sahyadri Speciality Hospital

Pune, 411004, India

Location

Christian Medical College

Vellore, 632004, India

Location

Azienda Ospedaliera Universitaria Careggi

Florence, 50134, Italy

Location

Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico

Milan, 20122, Italy

Location

Azienda Ospedaliera di Padova

Padua, 35128, Italy

Location

Università degli Studi di Roma "La Sapienza"

Roma, 00161, Italy

Location

Ospedale San Bortolo

Vicenza, 36100, Italy

Location

Nagoya University Hospital

Nagoya, 4668560, Japan

Location

Tokyo Medical University Hospital

Tokyo, 1600023, Japan

Location

Ogikubo Hospital

Tokyo, 167-0035, Japan

Location

Erasmus MC

Rotterdam, 3015 CE, Netherlands

Location

UMC Utrecht

Utrecht, 3584 CX, Netherlands

Location

Hematology and Transplantology Clinic, University Clinic Centre - Medical University Hospital

Gdansk, 80-952, Poland

Location

Nicolaus Copernicus Provincial Specialist Hospital in Lodz Department of Hematology

Krakow, 31-501, Poland

Location

Institute of Haematology and Transfusion Medicine

Warsaw, 02-776, Poland

Location

Independent Public Clinical Hospital No. 1 in Wroclaw, Department of Hematology, blood cancer and Bone Marrow Transplantation

Wroclaw, 50-367, Poland

Location

Kirov Hematology and Blood Transfusion Research Institute under the Federal Medical and Biological Agency of Russia

Kirov, 610027, Russia

Location

Territorial Clinical Hospital

Krasnoyarsk, 660022, Russia

Location

Municipal Policlinic # 37

Saint Petersburg, 195213, Russia

Location

Regional Pediatric Clinical Hospital #1

Yekaterinburg, 620149, Russia

Location

Hospital Materno Infantil Teresa Herrera

A Coruña, Galicia, 15006, Spain

Location

Hospital Universitario La Paz

Madrid, 28046, Spain

Location

Hospital Universitario La Paz

Palma de Mallorca, 07014, Spain

Location

Hospital Universitario Marques de Valdecilla

Santander, 39008, Spain

Location

Sahlgrenska Universitetssjukhuset

Gothenburg, 41345, Sweden

Location

Skåne University Hospital (SUS)

Malmo, Sweden

Location

The Royal London Hospital

London, E1 1BB, United Kingdom

Location

Royal Free Hospital

London, NW3 2QG, United Kingdom

Location

Hammersmith Hospital

London, W12 0NN, United Kingdom

Location

Manchester Royal Infirmary

Manchester, M13 9WL, United Kingdom

Location

Related Publications (1)

• Gill JC, Castaman G, Windyga J, Kouides P, Ragni M, Leebeek FW, Obermann-Slupetzky O, Chapman M, Fritsch S, Pavlova BG, Presch I, Ewenstein B. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood. 2015 Oct 22;126(17):2038-46. doi: 10.1182/blood-2015-02-629873. Epub 2015 Aug 3.

  PMID: 26239086 RESULT

MeSH Terms

Conditions

von Willebrand Diseases

Interventions

Sodium Chloride; Factor VIII

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Blood Platelet Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Protein Precursors; Biological Factors

Results Point of Contact

• Title: Study Director
• Organization: Shire

ClinicalTransparency@shire.com

+1 866 842 5335

Study Officials

• Study Director

  Takeda

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 4, 2011
• First Posted: August 5, 2011
• Study Start: November 1, 2011
• Primary Completion: February 1, 2014
• Study Completion: February 1, 2014
• Last Updated: May 19, 2021
• Results First Posted: April 21, 2016

Record last verified: 2021-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.

Locations

DE (3); JP (3); BE (2); NL (2); PL (4); CA (1); SE (2); ES (4); GB (4); BU (2); US (10); AU (1); IT (5); RU (4); IN (3)