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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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02932618
Recruitment Status : Recruiting
First Posted : October 13, 2016
Last Update Posted : July 17, 2020
Sponsor:
Collaborator:
Baxalta Innovations GmbH, now part of Shire
Information provided by (Responsible Party):
Takeda ( Baxalta now part of Shire )

Tracking Information
First Submitted Date  ICMJE October 12, 2016
First Posted Date  ICMJE October 13, 2016
Last Update Posted Date July 17, 2020
Actual Study Start Date  ICMJE December 18, 2017
Estimated Primary Completion Date June 30, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 15, 2020)
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).
Original Primary Outcome Measures  ICMJE
 (submitted: October 12, 2016)
Hemostatic Efficacy [ Time Frame: Within 24 hours of the beginning of a bleeding episode (BE) ]
Treatment success for rVWF-treated nonsurgical bleeding episodes (using a 4-point scale: Excellent, Good, Moderate, None)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 15, 2020)
  • Number of Treated Nonsurgical Bleeding Episodes with an Efficacy Rating of 'Excellent' or 'Good' [ Time Frame: Throughout the study duration of approximately 6 years ]
    If/when the severity and/or duration of the bleeding requires the infusion of the study drug.
  • Number of Infusions per Bleeding Episode [ Time Frame: Throughout the study duration of approximately 6 years ]
  • Number of Recombinant Von Willebrand Factor (rVWF), Units per Bleeding Episode [ Time Frame: Throughout the study duration of approximately 6 years ]
  • Number of ADVATE Units (if needed), per Bleeding Episode [ Time Frame: Throughout the study duration of approximately 6 years ]
  • 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.
  • 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.
  • 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.
  • 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.
  • Incidence and Severity of Adverse Events (AEs) [ Time Frame: Throughout the study period of approximately 6 years ]
  • Incidence of Thrombotic Events [ Time Frame: Throughout the study period of approximately 6 years ]
  • Incidence of Severe Hypersensitivity Reactions [ Time Frame: Throughout the study period of approximately 6 years ]
  • Development of Neutralizing Antibodies to von Willebrand Factor (VWF) and Factor VIII (FVIII) [ Time Frame: Throughout the study period of approximately 6 years ]
  • Development of Total Binding Antibodies to von Willebrand Factor (VWF) [ Time Frame: Throughout the study period of approximately 6 years ]
  • Development of Antibodies to Chinese Hamster Ovary (CHO) Proteins, Murine Immunoglobulin G (IgG), and rFurin [ Time Frame: Throughout the study period of approximately 6 years ]
  • 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, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]
  • 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, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]
  • Mean Residence Time (MRT) [ Time Frame: Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]
  • Time to Reach Maximal Plasma Concentration (Tmax) [ Time Frame: Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]
    Tmax will be assessed.
  • Maximal Plasma Concentration (Cmax) [ Time Frame: Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]
    Cmax will be assessed.
  • Clearance (CL) [ Time Frame: Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]
  • Incremental Recovery (IR) [ Time Frame: Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]
  • In-vivo Recovery (IVR) [ Time Frame: Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]
  • Elimination Phase Half-life (T1/2) [ Time Frame: Within 30 minutes prior to infusion and post infusion at: SEQUENCE 1: 1, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]
  • 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, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]
  • 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, 24, 72 hours; SEQUENCE 2: 0.25, 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).
  • 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, 24, 72 hours; SEQUENCE 2: 0.25, 12, and 48 hours; SEQUENCE 3: 6, 30, and 96 hours ]
Original Secondary Outcome Measures  ICMJE
 (submitted: October 12, 2016)
  • Number of Treated Nonsurgical Bleeding Episodes with an Efficacy Rating of 'Excellent' or 'Good' [ Time Frame: Within 24 hours of the beginning of a bleeding episode (BE) ]
  • Number of Infusions per Bleeding Episode [ Time Frame: Within 24 hours of the beginning of a bleeding episode (BE) ]
  • Number of rVWF Units per Bleeding Episode [ Time Frame: Within 24 hours of the beginning of a bleeding episode (BE) ]
  • Number of ADVATE Units (if needed), per Bleeding Episode [ Time Frame: Within 24 hours of the beginning of a bleeding episode (BE) ]
  • Elective surgery: Overall Assessment of Hemostatic Efficacy 24 hours After the Last Perioperative Infusion of rVWF [ Time Frame: 24 hours after the last perioperative infusion of rVWF ]
    Assessed by the Investigator (hematologist) on a 4-point ordinal scale: Excellent, Good, Moderate, None
  • Incidence and severity of adverse events (AEs) by system organ class (SOC) and preferred term [ Time Frame: Throughout the study period of approximately 2 years, 9 months ]
  • Incidence of Thrombotic Events [ Time Frame: Throughout the study period of approximately 2 years, 9 months ]
  • Incidence of Severe Hypersensitivity Reactions [ Time Frame: Throughout the study period of approximately 2 years, 9 months ]
  • Development of Neutralizing Antibodies to VWF and FVIII [ Time Frame: Throughout the study period of approximately 2 years, 9 months ]
  • Development of Total Binding Antibodies to VWF [ Time Frame: Throughout the study period of approximately 2 years, 9 months ]
  • Development of Antibodies to CHO Proteins, Murine IgG, and rFurin [ Time Frame: Throughout the study period of approximately 2 years, 9 months ]
  • Pharmacokinetics: 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 ]
  • Pharmacokinetics: Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞) [ 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 ]
  • Pharmacokinetics: 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 ]
  • Pharmacokinetics: 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 ]
  • 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 ]
  • 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 ]
  • 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 ]
  • Volume of distribution at steady state (Vss) for VWF:RCo [ 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 ]
  • 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)
  • 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 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE BAX 111 rVWF in Pediatrics
Official Title  ICMJE 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
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
Detailed Description

18 JUN 2020: The temporary enrollment stop of new patients into this study due to the COVID-10 pandemic has been lifted in one or more countries/sites, and the study is now again enrolling new patients. However, some countries/sites may still have paused the enrollment of new patients due to the pandemic.

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Von Willebrand Disease
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Experimental: On-demand Treatment
    Participants will receive treatment for non-surgical bleeding episodes over a 12 to 18-month period.
    Interventions:
    • Biological: von Willebrand factor (Recombinant)
    • Biological: Antihemophilic Factor (Recombinant)
  • 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.
    Interventions:
    • Biological: von Willebrand factor (Recombinant)
    • Biological: Antihemophilic Factor (Recombinant)
  • 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.
    Interventions:
    • Biological: von Willebrand factor (Recombinant)
    • Biological: Antihemophilic Factor (Recombinant)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: July 15, 2020)
34
Original Estimated Enrollment  ICMJE
 (submitted: October 12, 2016)
39
Estimated Study Completion Date  ICMJE December 31, 2022
Estimated Primary Completion Date June 30, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

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

    1. Type 1 (VWF:RCo < 20 International Units per deciliter [IU/dL]); or
    2. Type 2A (VWF:RCo < 20 IU/dL), Type 2B (as diagnosed by genotype), Type 2N (Factor VIII coagulation activity [FVIII:C] < 10 % and historically documented genetics), Type 2M; or
    3. 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 legally authorized representative are willing and able to comply with the requirements of the protocol, which should also be confirmed based on a pre-screening evaluation held between the Investigator and the Sponsor, to ensure no eminent risk is present that could challenge the participants compliance with the study requirements.

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 von Willebrand disease (pdVWF).

Additional inclusion criterion for previously untreated participants are as follows:

  • The participant has not received prior VWF coagulation factor replacement therapy.
  • Pediatric participants in the continuation study (SHP677-304 [NCT03879135]) that require elective or emergency surgical/invasive treatment during their participation in the continuation study may be considered for enrollment in this study's surgery arm to receive treatment with the study drug (rVWF) for peri-operative management of surgery related bleeds/bleeding tendency, if they continue meeting all other eligibility criteria for the surgery arm in this Pediatric On-Demand and Surgery study, 071102.

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/ cubic millimeter (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 other than rVWF or investigational device during the course of this study.
  • Participant's legal representative is a family member or employee of the Investigator.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Shire Contact +1 866 842 5335 clinicaltransparency@shire.com
Listed Location Countries  ICMJE Austria,   Belgium,   Czechia,   France,   Germany,   Italy,   Netherlands,   Russian Federation,   Spain,   Turkey,   Ukraine,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02932618
Other Study ID Numbers  ICMJE 071102
2016-001477-33 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: 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
Responsible Party Takeda ( Baxalta now part of Shire )
Study Sponsor  ICMJE Baxalta now part of Shire
Collaborators  ICMJE Baxalta Innovations GmbH, now part of Shire
Investigators  ICMJE
Study Director: Study Director Shire
PRS Account Takeda
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP