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Completed

NCT Number: NCT01736475

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

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.

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Key information

Conditions

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

Age range

12 year–65 year

Sex eligibility

Male

Study type

Interventional

Phase

Phase 2 / Phase 3

Primary location

Royal Adelaide Hospital, Adelaide, South Australia, Australia

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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).

Treatment and study plan

Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method

Biological

Pharmacokinetic (PK) evaluation of ADVATE

Other names: ADVATE

PEGylated Recombinant Factor VIII

Biological

Pharmacokinetic (PK) evaluation of BAX 855

Other names: BAX 855

Primary outcomes

  1. Annualized Bleeding Rate (ABR)

    Time frame: 9 months

    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 outcomes

  1. 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.

    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.

  2. 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].

  3. 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].

    Interval between Bleeds in months was calculated as: Observation period for efficacy (in days)/(number of bleeds)*(12/365.2425)

  4. 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

  5. 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.

    Infusions per bleeding episode for maintenance of hemostasis only includes infusions following the resolution of a bleed to maintain hemostasis.

  6. 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].

    Adverse Events (AEs) and Serious Adverse Events (SAEs)

  7. 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].

    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

  8. 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].

    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.

  9. 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]

    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.

  10. 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).

    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).

  11. 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).

    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).

  12. 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).

    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).

  13. 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).

    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).

  14. 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).

    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).

  15. 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).

    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).

  16. 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).

    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).

  17. 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).

    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).

  18. Change in Vital Signs From Screening - Temperature

    Time frame: Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination

  19. Change in Vital Signs From Screening - Pulse Rate

    Time frame: Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination

  20. Change in Vital Signs From Screening - Respiratory Rate

    Time frame: Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination

  21. Changes in Vital Signs From Screening - Blood Pressure

    Time frame: Screening, week 2, week 4, exposure day 10-15, month 3, study completion/termination

    Systolic Blood Pressure (SBP) Diastolic Blood Pressure (DBP)

  22. Changes in Clinical Chemistry Laboratory Assessments From Screening - Albumin and Protein

    Time frame: Screening, week 2, week 4, month 3, study completion/termination

  23. 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

    Alkaline Phosphatase (Alk Phos); Alanine Aminotransferase (Ala Amino); Aspartate Aminotransferase (Asp Amino)

  24. 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

  25. Changes in Clinical Chemistry Laboratory Assessments From Screening - Creatinine, and Bilirubin

    Time frame: Screening, week 2, week 4, month 3, study completion/termination

  26. 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

  27. Changes in Hematology Laboratory Assessments From Screening - Hematocrit

    Time frame: Screening, week 2, week 4, month 3, study completion/termination

  28. Changes in Hematology Laboratory Assessments From Screening - Hemoglobin

    Time frame: Screening, week 2, week 4, month 3, study completion/termination

  29. Changes in Hematology Laboratory Assessments From Screening - Erythrocytes

    Time frame: Screening, week 2, week 4, month 3, study completion/termination

  30. 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

Sponsors and collaborators

Lead sponsor

Baxalta now part of Shire

Industry

Registry information

Official study 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

Important dates

Study start
2013
Primary completion
2014
Study completion
2014
First posted
Nov 29, 2012
Registry last updated
May 20, 2021

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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