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BAX 111 rVWF in Pediatrics

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02932618
Recruitment Status : Active, not recruiting
First Posted : October 13, 2016
Last Update Posted : May 6, 2020
Sponsor:
Collaborator:
Baxalta Innovations GmbH, now part of Shire
Information provided by (Responsible Party):
Shire ( Baxalta now part of Shire )

Brief Summary:

The purpose of this study in pediatric participants (<18 years of age) with severe hereditary von Willebrand disease (VWD) is:

  1. To assess the efficacy, safety, and tolerability of recombinant von Willebrand Factor (rVWF), with or without ADVATE, in the treatment and control of nonsurgical bleeding events
  2. To assess the efficacy and safety of rVWF with ADVATE during elective or emergency surgery
  3. To determine the pharmacokinetic (PK) profile of rVWF

Condition or disease Intervention/treatment Phase
Von Willebrand Disease Biological: von Willebrand factor (Recombinant) Biological: Antihemophilic Factor (Recombinant) Phase 3

Detailed Description:
23 APRIL 2020: Enrollment of new patients into this study has been paused due to the COVID-19 situation. The duration of this pause is dependent on the leveling and control of the COVID-19 pandemic.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 39 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 3, Prospective, Multicenter, Uncontrolled, Open-Label Clinical Study to Determine the Efficacy, Safety, and Tolerability of rVWF With or Without ADVATE in the Treatment and Control of Bleeding Episodes, the Efficacy and Safety of rVWF in Elective and Emergency Surgeries, and the Pharmacokinetics (PK) of rVWF in Children Diagnosed With Severe Von Willebrand Disease
Actual Study Start Date : December 18, 2017
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: On-demand Treatment
Participants will receive treatment for non-surgical bleeding episodes over a 12 to 18-month period.
Biological: von Willebrand factor (Recombinant)
Lyophilized powder and solvent to prepare solution for injection.
Other Names:
  • VONVENDI
  • rVWF
  • BAX111
  • BAX 111

Biological: Antihemophilic Factor (Recombinant)
Packaged in single boxes with 2 glass vials, with one vial containing the lyophilized ADVATE and the second vial containing the diluent.
Other Names:
  • ADVATE
  • Recombinant Factor VIII
  • rFVIII

Experimental: Elective Surgery
12-24 hours prior to surgery and within 3 hours of surgery. Minor surgery: infuse every 12-24 hours for at least 48 hours. Oral Surgery: infuse at least once within first 8-12 hours post-surgery. Major Surgery: infuse every 12-24 hours for at least first 72 hours post-surgery.
Biological: von Willebrand factor (Recombinant)
Lyophilized powder and solvent to prepare solution for injection.
Other Names:
  • VONVENDI
  • rVWF
  • BAX111
  • BAX 111

Biological: Antihemophilic Factor (Recombinant)
Packaged in single boxes with 2 glass vials, with one vial containing the lyophilized ADVATE and the second vial containing the diluent.
Other Names:
  • ADVATE
  • Recombinant Factor VIII
  • rFVIII

Experimental: Emergency Surgery
Within 3 hours prior to surgery. Minor surgery: infuse every 12-24 hours for at least 48 hours. Oral Surgery: infuse at least once within first 8-12 hours post-surgery. Major Surgery: infuse every 12-24 hours for at least first 72 hours post-surgery.
Biological: von Willebrand factor (Recombinant)
Lyophilized powder and solvent to prepare solution for injection.
Other Names:
  • VONVENDI
  • rVWF
  • BAX111
  • BAX 111

Biological: Antihemophilic Factor (Recombinant)
Packaged in single boxes with 2 glass vials, with one vial containing the lyophilized ADVATE and the second vial containing the diluent.
Other Names:
  • ADVATE
  • Recombinant Factor VIII
  • rFVIII




Primary Outcome Measures :
  1. Hemostatic Efficacy [ Time Frame: Within 24 hours after the last infusion of study drug following the onset of the bleeding episode (if/when the severity and/or duration of the bleeding requires the infusion of the study drug) ]
    Treatment success for rVWF-treated nonsurgical bleeding episodes (using a 4-point scale: Excellent, Good, Moderate, None)


Secondary Outcome Measures :
  1. Number of Treated Nonsurgical Bleeding Episodes with an Efficacy Rating of 'Excellent' or 'Good' [ Time Frame: Throughout the study duration of approximately 4 years ]
    If/when the severity and/or duration of the bleeding requires the infusion of the study drug

  2. Number of Infusions per Bleeding Episode [ Time Frame: Throughout the study duration of approximately 4 years ]
  3. Number of rVWF Units per Bleeding Episode [ Time Frame: Throughout the study duration of approximately 4 years ]
  4. Number of ADVATE Units (if needed), per Bleeding Episode [ Time Frame: Throughout the study duration of approximately 4 years ]
  5. Elective or emergency surgery assessment of hemostatic efficacy - immediately after surgery [ Time Frame: Immediately after surgery ]
    Assessed by by the operating surgeon, based on a 4-point ordinal scale: Excellent, Good, Moderate, None.

  6. Elective or emergency surgery: Overall Assessment of Hemostatic Efficacy 24 hours After the Last Perioperative Infusion of rVWF [ Time Frame: 24 hours after last perioperative rVWF infusion ]
    Assessed by the Investigator (hematologist) on a 4-point ordinal scale: Excellent, Good, Moderate, None.

  7. Elective or emergency surgery: Overall Assessment of Hemostatic Efficacy Day 7 post-operative [ Time Frame: Post-operative Day 7 ]
    Assessed by the Investigator (hematologist) on a 4-point ordinal scale: Excellent, Good, Moderate, None.

  8. Elective or emergency surgery: Overall Assessment of Hemostatic Efficacy Day 14 post-operative [ Time Frame: Post-operative Day 14 ]
    Assessed by the Investigator (hematologist) on a 4-point ordinal scale: Excellent, Good, Moderate, None.

  9. Incidence of Severe Hypersensitivity Reactions [ Time Frame: Throughout the study period of approximately 4 years ]
  10. Incidence and Severity of Adverse Events (AEs) [ Time Frame: Throughout the study period of approximately 4 years ]
  11. Incidence of Thrombotic Events [ Time Frame: Throughout the study period of approximately 4 years ]
  12. Development of Neutralizing Antibodies to VWF and FVIII [ Time Frame: Throughout the study period of approximately 4 years ]
  13. Development of Total Binding Antibodies to VWF [ Time Frame: Throughout the study period of approximately 4 years ]
  14. Development of Antibodies to CHO Proteins, Murine IgG, and rFurin [ Time Frame: Throughout the study period of approximately 4 years ]
  15. Area Under the Plasma Concentration/Time Curve From 0 to 96 Hours Post-Infusion (AUC0-96h) [ Time Frame: Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 2, 72 hours; SEQUENCE 2: 15 minutes, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]
  16. Area Under the Plasma Concentration/Time Curve From Time 0 to Infinity (AUC0-inf) [ Time Frame: Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 2, 72 hours; SEQUENCE 2: 15 minutes, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]
  17. Mean Residence Time (MRT) [ Time Frame: Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 2, 72 hours; SEQUENCE 2: 15 minutes, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]
  18. Time to Reach Maximal Plasma Concentration (Tmax) [ Time Frame: Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 2, 72 hours; SEQUENCE 2: 15 minutes, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]
    Tmax will be assessed.

  19. Maximal Plasma Concentration (Cmax) [ Time Frame: Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 2, 72 hours; SEQUENCE 2: 15 minutes, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]
    Cmax will be assessed.

  20. Clearance (CL) [ Time Frame: Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 2, 72 hours; SEQUENCE 2: 15 minutes, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]
  21. Incremental Recovery (IR) [ Time Frame: Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 2, 72 hours; SEQUENCE 2: 15 minutes, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]
  22. In-vivo Recovery (IVR) [ Time Frame: Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 2, 72 hours; SEQUENCE 2: 15 minutes, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]
  23. Elimination Phase Half-life (T1/2) [ Time Frame: Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 2, 72 hours; SEQUENCE 2: 15 minutes, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]
  24. Volume of Distribution at Steady State (Vss) for VWF:RCo, VWF:Ag and VWF:CB [ Time Frame: Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 2, 72 hours; SEQUENCE 2: 15 minutes, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]
  25. Area Under the Plasma Concentration/Time Curve from 0 to 96 Hours Post-infusion (AUC0-96h) for VWF:Ag and VWF:CB [ Time Frame: Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 2, 72 hours; SEQUENCE 2: 15 minutes, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]
    von Willebrand factor: antigen (VWF:Ag); von Willebrand factor: collagen binding capacity (VWF:CB).

  26. Area Under the Plasma Concentration/Time Curve From 0 to 96 Hours Post-infusion (AUC0-96h) for Factor VIII (FVIII) Activity [ Time Frame: Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 2, 72 hours; SEQUENCE 2: 15 minutes, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of severe von Willebrand disease (VWD) (defined as von Willebrand factor: ristocetin cofactor [VWF:RCo] less than [<] 20%):

    • Type 1 (VWF:RCo < 20 International Units per deciliter [IU/dL]); or
    • Type 2A (VWF:RCo < 20 IU/dL), Type 2B (as diagnosed by genotype), Type 2N (Factor VIII coagulation activity [FVIII:C] <10 percent [%] and historically documented genetics), Type 2M; or
    • Type 3 (VWF:Ag less than or equal to [=<] 3 IU/dL).
  • Age 0 to < 18 years at the time of Screening.
  • The participant has provided assent (if appropriate) and legally authorized representative(s) has provided informed consent.
  • If female of childbearing potential, participant presents with a negative serum pregnancy test.
  • If applicable, participant agrees to employ adequate birth control measures for the duration of the study.
  • The participant and/or the legal representative is willing and able to comply with the requirements of the protocol.

Additional inclusion criteria for previously treated participants and participants undergoing surgery are as follows:

  • Unable to tolerate or are inadequately responsive to deamino-delta-D-arginine vasopressin.
  • The participant has had a minimum of 1 documented bleed requiring VWF coagulation factor replacement therapy (i.e. treatment with a VWF product) during the previous 12 months prior to enrollment and overall historically 3 or more exposure days (EDs) to plasma-derived VWF.

Additional inclusion criterion for previously untreated participants are as follows:

- The participant has not received prior VWF coagulation factor replacement therapy.

Exclusion Criteria:

  • Diagnosis of pseudo-VWD or another hereditary or acquired coagulation disorder (eg, qualitative and quantitative platelet disorders or elevated prothrombin time [PT]/international normalized ratio [INR] greater than [>] 1.4).
  • History or presence of a VWF inhibitor at Screening.
  • History or presence of a Factor VIII (FVIII) inhibitor with a titer greater than or equal [>=] 0.4 Bethesda units (BU) (by Nijmegen assay) or >= 0.6 BU (by Bethesda assay).
  • Documented history of a VWF: RCo half-life < 6 hours.
  • Known hypersensitivity to any of the components of the study drug, such as mouse or hamster proteins.
  • Medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis/asthma, food allergies, or animal allergies.
  • Medical history of a thromboembolic event.
  • Human immunodeficiency virus (HIV) positive, with an absolute CD4 count < 200/ mm^3.
  • In the judgment of the Investigator, the participant has another clinically significant concomitant disease (e.g. uncontrolled hypertension, cancer) that may pose additional risks for the participant.
  • Diagnosis of significant liver disease, as evidenced by, but not limited to, any of the following: serum alanine aminotransferase (ALT) of 5 times the upper limit of normal; hypoalbuminemia; portal vein hypertension (e.g. presence of otherwise unexplained splenomegaly, history of esophageal varices) or liver cirrhosis classified as Child B or C.
  • Diagnosis of renal disease, with a serum creatinine level >= 2.5 milligram per deciliter (mg/dL).
  • Immunomodulatory drug treatment other than anti-retroviral chemotherapy (e.g. α-interferon, or corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 milligram per day [mg/day] (excluding topical treatment [e.g. ointments, nasal sprays]), within 30 days prior to signing the informed consent (or assent, if appropriate).
  • If female, participant is pregnant or lactating at the time informed consent (or assent, if appropriate) is obtained.
  • Participant has participated in another clinical study involving an investigational product (IP), other than recombinant von Willebrand Factor (rVWF) with or without ADVATE, or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study.
  • Participant's legal representative is a family member or employee of the Investigator

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02932618


Locations
Show Show 46 study locations
Sponsors and Collaborators
Baxalta now part of Shire
Baxalta Innovations GmbH, now part of Shire
Investigators
Layout table for investigator information
Study Director: Study Director Shire

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Responsible Party: Baxalta now part of Shire
ClinicalTrials.gov Identifier: NCT02932618    
Other Study ID Numbers: 071102
2016-001477-33 ( EudraCT Number )
First Posted: October 13, 2016    Key Record Dates
Last Update Posted: May 6, 2020
Last Verified: May 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Shire provides access to the de-identified individual participant data for eligible studies to aid qualified researchers in addressing legitimate scientific objectives. These IPDs will be provided following approval of a data sharing request, and under the terms of a data sharing agreement.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described in the Data Sharing section of the www.shiretrials.com website. 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.
URL: https://www.shiretrials.com/en/our-commitment-to-transparency/data-sharing-with-researchers

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Von Willebrand Diseases
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Blood Platelet Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Factor VIII
Coagulants