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Study Investigating a PEGylated Recombinant Factor VIII (BAX 855) for Hemophilia A (PROLONG-ATE Study)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Baxalta US Inc.
ClinicalTrials.gov Identifier:
NCT01736475
First received: November 21, 2012
Last updated: July 22, 2016
Last verified: July 2016
  Purpose
To assess efficacy and safety, including immunogenicity of BAX 855 administered as prophylaxis and as on-demand therapy in adult and adolescent (12-65 years) previously treated patients (PTPs) with severe hemophilia A To determine the pharmacokinetic (PK) parameters of BAX 855.

Condition Intervention Phase
Hemophilia A
Biological: Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method
Biological: PEGylated Recombinant Factor VIII
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: A Phase 2/3, Multi-Center, Open Label Study of Efficacy, Safety, and Pharmacokinetics of PEGylated Recombinant Factor VIII (BAX 855) Administered for Prophylaxis and Treatment of Bleeding in Previously Treated Patients With Severe Hemophilia A

Resource links provided by NLM:


Further study details as provided by Baxalta US Inc.:

Primary Outcome Measures:
  • Annualized Bleeding Rate (ABR) [ Time Frame: 9 months ] [ Designated as safety issue: No ]
    Comparisons between prophylactic and on-demand treatment were based on ABR estimates from a negative binomial regression model, taking into account the treatment regimen, target joints and age at screening, and duration of the observation period for efficacy.


Secondary Outcome Measures:
  • Rate of Success of BAX 855 for Treatment of Bleeding Episodes [ Time Frame: At least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm. ] [ Designated as safety issue: No ]
    Success in the control of bleeding was defined as a rating of excellent or good using the Efficacy Rating Scale for Treatment of Bleeding Episodes measured 24 hours after initiation of treatment for the bleeding episode. EXCELLENT: Full relief of pain and cessation of objective signs of bleeding (eg, swelling, tenderness, and decreased range of motion in the case of musculoskeletal hemorrhage) after a single infusion. No additional infusion is required for the control of bleeding. Administration of further infusions to maintain hemostasis would not affect this scoring. GOOD: Definite pain relief and/or improvement in signs of bleeding after a single infusion. Possibly requires more than 1 infusion for complete resolution. FAIR: Probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion. Required more than 1 infusion for complete resolution. NONE: No improvement or condition worsens.

  • Average Number of BAX 855 Infusions Needed for the Treatment of Bleeding Episodes [ Time Frame: From first exposure to BAX 855 until the end of the study, [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm; and 6 months (± 2 weeks) for the on-demand arm]. ] [ Designated as safety issue: No ]
  • Number of Participants With ≤1, 2, 3, 4, 5, 6, or >6 Month Time Intervals Between Bleeding Episodes or no Bleeding Episodes [ Time Frame: From first exposure to BAX 855 until the end of the study, [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm; and 6 months (± 2 weeks) for the on-demand arm]. ] [ Designated as safety issue: No ]
    Interval between Bleeds in months was calculated as: Observation period for efficacy (in days)/(number of bleeds)*(12/365.2425)

  • Weight-adjusted Consumption of BAX 855 - Per Prophylactic Infusion and Pharmacokinetic (PK) Infusion [ Time Frame: Prophylactic Infusion: ≥50 exposure days or 6 months (±2 weeks), whichever occurs last. PK Infusion: PK #1 Pre-infusion within 30 minutes; Post-infusion 10 min, and 0.5, 1, 3, 6, 24, 32, 48, 56 hours (h). PK #2 also at Post-infusion 96h ] [ Designated as safety issue: No ]
  • Weight-adjusted Consumption of BAX 855 - Per Treatment of Bleeding Episode (BE) and Per BE for Maintenance of Hemostasis [ Time Frame: Treatment of Bleeding Episode (BE): Minor/Moderate BE every 12 to 24 hours until bleeding is resolved; Major BE every 8 to 12 hours until bleeding is resolved. Per BE for Maintenance of Hemostasis: within 48 hours after bleeding episode resolution. ] [ Designated as safety issue: No ]
    Infusions per bleeding episode for maintenance of hemostasis only includes infusions following the resolution of a bleed to maintain hemostasis.

  • Percentage of Participants With Adverse Events [ Time Frame: From first exposure to BAX 855 until the end of the study, [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm; and 6 months (± 2 weeks) for the on-demand arm]. ] [ Designated as safety issue: Yes ]
    Adverse Events (AEs) and Serious Adverse Events (SAEs)

  • Immunogenicity - Number of Participants With Positive Inhibitory Antibodies to FVIII, Binding Antibodies to FVIII, PEG-VIII, PEG and Anti-CHO Antibodies at Study Completion/Termination [ Time Frame: From first exposure to BAX 855 until the end of the study, [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm; and 6 months (± 2 weeks) for the on-demand arm]. ] [ Designated as safety issue: Yes ]

    Number of participants who received BAX855, with immunogenicity data from study completion/termination visit.

    FVIII = factor VIII; PEG-VIII = polyethylene glycol-factor VIII; Anti-CHO = Anti-Chinese hamster ovary


  • Patient Reported Outcomes: Haemo-SYM Questionnaire, Change in Score From Baseline to End of Study [ Time Frame: Baseline; and end of study visit [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm]. ] [ Designated as safety issue: No ]

    The HAEMO-SYM has two subscales: pain and bleeds. HAEMO-SYM subscale scores are calculated by taking the mean of the items in each subscale and transforming them to a 0 (none or absent) to 100 (very severe) scale.

    Given that higher scores indicate more severe symptoms on the Haemo-SYM and that the change scores were calculated as the value at study completion minus the value at baseline, a negative change score indicates an improvement (reduction in symptoms). Conversely, a positive change score indicates worsening symptoms.


  • Patient Reported Outcomes - Short Form (SF)-36, Change From Baseline to End of Study [ Time Frame: Baseline; and end of study visit [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm] ] [ Designated as safety issue: No ]
    Change from Baseline to End of Study for SF-36 Questionnaire is provided. Scores for individual SF-36 categories range from 0 to 100 with higher scores representing better health. Given that higher scores indicate better health-related quality of life (HRQoL) and that the change scores were calculated as the value at study completion minus the value at baseline, a negative change score indicates a worsening of HRQoL.

  • Pharmacokinetics (Pk) - Plasma Half-life (One-stage Clotting Assay) [ Time Frame: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only). ] [ Designated as safety issue: No ]

    Terminal half-life calculated as log_e2/λz where λz is the terminal elimination rate constant.

    Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).


  • Pharmacokinetics (Pk) - Mean Residence Time (One-stage Clotting Assay) [ Time Frame: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only). ] [ Designated as safety issue: No ]

    The mean residence time (MRT) w as calculated as total area under the moment curve divided by the total area under the curve starting from the begin of infusion (or the end of infusion if start time is not available).

    Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).


  • Pharmacokinetics (Pk) - Total Body Clearance (One-stage Clotting Assay) [ Time Frame: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only). ] [ Designated as safety issue: No ]

    Clearance in dL/(kg.h) will be calculated as the dose in IU/kg divided by the total area under the curve starting from the begin of infusion (or the end of infusion if start time is not available).

    Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).


  • Pharmacokinetics (Pk) - Incremental Recovery Over Time (One-stage Clotting Assay) [ Time Frame: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only). ] [ Designated as safety issue: No ]

    Incremental recovery (IR) in (IU/dL)/ (IU/kg) calculated as: IR = (Cmax- (C pre-infusion)) / (Dose/kg), where C =concentration.

    Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).


  • Pharmacokinetics (Pk) - Area Under the Concentration Versus Time Curve From 0 to Infinity (AUC0-∞) (One-stage Clotting Assay) [ Time Frame: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only). ] [ Designated as safety issue: No ]

    Calculated by WinNonlin NCA (Model 201, calculation method: Linear Trapezoidal Linear/Log Interpolation).

    Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).


  • Pharmacokinetics (Pk) - Apparent Volume of Distribution at Steady State (Vss) (One-stage Clotting Assay) [ Time Frame: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only). ] [ Designated as safety issue: No ]

    The apparent volume of distribution at steady state (Vss) will be calculated as: Vss = Clearance * Mean Residence Time.

    Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).


  • Pharmacokinetics (Pk) - Maximum Plasma Concentration (Cmax) (One-stage Clotting Assay) [ Time Frame: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only). ] [ Designated as safety issue: No ]
    Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).

  • Pharmacokinetics (Pk) -Time to Maximum Concentration in Plasma (Tmax) (One-stage Clotting Assay) [ Time Frame: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only). ] [ Designated as safety issue: No ]
    Tmax in hours will be defined as the time to reach Cmax. Participants in the pharmacokinetic full analysis set (PKFAS) analysis set received an initial infusion of ADVATE for pharmacokinetic analysis (PK-1) followed by a washout period and an infusion of BAX 855 for a second pharmacokinetic analysis (PK-2). After at least 50 EDs of BAX 855, participants in the PK subgroup received another infusion of BAX 855 for pharmacokinetic analysis (PK-3).

  • Change in Vital Signs From Screening - Temperature [ Time Frame: Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination ] [ Designated as safety issue: Yes ]
  • Change in Vital Signs From Screening - Pulse Rate [ Time Frame: Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination ] [ Designated as safety issue: Yes ]
  • Change in Vital Signs From Screening - Respiratory Rate [ Time Frame: Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination ] [ Designated as safety issue: Yes ]
  • Changes in Vital Signs From Screening - Blood Pressure [ Time Frame: Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination ] [ Designated as safety issue: Yes ]
    Systolic Blood Pressure (SBP) Diastolic Blood Pressure (DBP)

  • Changes in Clinical Chemistry Laboratory Assessments From Screening - Albumin and Protein [ Time Frame: Screening, week 2, week 4, month 3, study completion/termination ] [ Designated as safety issue: Yes ]
  • Changes in Clinical Chemistry Laboratory Assessments From Screening - Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase [ Time Frame: Screening, week 2, week 4, month 3, study completion/termination ] [ Designated as safety issue: Yes ]
    Alkaline Phosphatase (Alk Phos); Alanine Aminotransferase (Ala Amino); Aspartate Aminotransferase (Asp Amino)

  • Changes in Clinical Chemistry Laboratory Assessments From Screening - Bicarbonate, Chloride, Glucose, Potassium, Sodium, Blood Urea Nitrogen (BUN) [ Time Frame: Screening, week 2, week 4, month 3, study completion/termination ] [ Designated as safety issue: Yes ]
  • Changes in Clinical Chemistry Laboratory Assessments From Screening - Creatinine, and Bilirubin [ Time Frame: Screening, week 2, week 4, month 3, study completion/termination ] [ Designated as safety issue: Yes ]
  • Changes in Hematology Laboratory Assessments From Screening - Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils, Platelets, and Leukocytes [ Time Frame: Screening, week 2, week 4, month 3, study completion/termination ] [ Designated as safety issue: Yes ]
  • Changes in Hematology Laboratory Assessments From Screening - Hematocrit [ Time Frame: Screening, week 2, week 4, month 3, study completion/termination ] [ Designated as safety issue: Yes ]
  • Changes in Hematology Laboratory Assessments From Screening - Hemoglobin [ Time Frame: Screening, week 2, week 4, month 3, study completion/termination ] [ Designated as safety issue: Yes ]
  • Changes in Hematology Laboratory Assessments From Screening - Erythrocytes [ Time Frame: Screening, week 2, week 4, month 3, study completion/termination ] [ Designated as safety issue: Yes ]
  • Changes in Lipid Panel Assessments From Screening - Cholesterol; High Density Lipoprotein (HDL); Low Density Lipoprotein (LDL); Triglycerides; and Very Low Density Lipoprotein (VLDL) [ Time Frame: Screening, week 2, week 4, month 3, study completion/termination ] [ Designated as safety issue: Yes ]

Enrollment: 159
Study Start Date: January 2013
Study Completion Date: July 2014
Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Prophylaxis Biological: Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method
Pharmacokinetic (PK) evaluation of ADVATE
Other Name: ADVATE
Biological: PEGylated Recombinant Factor VIII
Pharmacokinetic (PK) evaluation of BAX 855
Other Name: BAX 855
Biological: PEGylated Recombinant Factor VIII
Prophylaxis treatment
Other Name: BAX 855
Experimental: On-demand Biological: PEGylated Recombinant Factor VIII
On-demand treatment
Other Name: BAX 855

  Eligibility

Ages Eligible for Study:   12 Years to 65 Years   (Child, Adult)
Genders Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Main Inclusion Criteria:

  • Participant and/or legal representative has/have voluntarily provided signed informed consent
  • Participant is 12 to 65 years old at the time of screening
  • Participant is male with severe hemophilia A (Factor VIII (FVIII) clotting activity < 1%) as confirmed by central laboratory at screening after the appropriate washout period or a documented FVIII clotting activity <1%
  • Participant has been previously treated with plasma-derived FVIII concentrates or recombinant FVIII for ≥150 documented exposure days (EDs)
  • Participant is currently receiving prophylaxis or on-demand therapy with FVIII
  • Participant is willing and able to comply with the requirements of the protocol

Main Exclusion Criteria:

  • Participant has detectable FVIII inhibitory antibodies (≥ 0.6 Bethesda Units (BU) using the Nijmegen modification of the Bethesda assay) as confirmed by central laboratory at screening
  • Participant has history of FVIII inhibitory antibodies (≥ 0.4 BU using the Nijmegen modification of the Bethesda assay or ≥ 0.6 BU using the Bethesda assay) at any time prior to screening
  • Participant has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (eg, qualitative platelet defect or von Willebrand's disease).
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01736475

  Show 72 Study Locations
Sponsors and Collaborators
Baxalta US Inc.
Investigators
Study Director: Brigitt Abbuehl, MD Baxter Innovations GmbH
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Baxalta US Inc.
ClinicalTrials.gov Identifier: NCT01736475     History of Changes
Other Study ID Numbers: 261201  2012-003599-38 
Study First Received: November 21, 2012
Results First Received: March 4, 2016
Last Updated: July 22, 2016
Health Authority: Netherlands: Medicines Evaluation Board (MEB)
Germany: Paul-Ehrlich-Institut
Korea: Food and Drug Administration
United States: Food and Drug Administration
Czech Republic: State Institute for Drug Control
Lithuania: State Medicine Control Agency - Ministry of Health
Austria: Agency for Health and Food Safety
Malaysia: Ministry of Health
Ukraine: State Pharmacological Center - Ministry of Health
Japan: Pharmaceuticals and Medical Devices Agency
Australia: Department of Health and Ageing Therapeutic Goods Administration
Israel: Israeli Health Ministry Pharmaceutical Administration
Switzerland: Federal Office of Public Health
Sweden: Medical Products Agency
Bulgaria: Bulgarian Drug Agency
Taiwan: Department of Health
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Additional relevant MeSH terms:
Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Factor VIII
Coagulants

ClinicalTrials.gov processed this record on September 30, 2016