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BAX 855 PK-guided Dosing (PROPEL)

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: NCT02585960
Recruitment Status : Completed
First Posted : October 26, 2015
Results First Posted : August 26, 2019
Last Update Posted : September 12, 2019
Sponsor:
Collaborator:
Baxalta Innovations GmbH, now part of Shire
Information provided by (Responsible Party):
Shire ( Baxalta now part of Shire )

Brief Summary:
  1. To compare the efficacy and safety of pharmacokinetic (PK)-guided treatment with BAX 855 targeting FVIII trough levels of 1-3% and approximately 10% (8-12%)
  2. To further characterize pharmacokinetic (PK) and pharmacodynamic (PD) parameters of BAX 855

Condition or disease Intervention/treatment Phase
Hemophilia A Biological: PEGylated Recombinant Factor VIII Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 135 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Phase 3, Prospective, Randomized, Multi-center Clinical Study Comparing the Safety and Efficacy of BAX 855 Following PK-guided Prophylaxis Targeting Two Different FVIII Trough Levels in Subjects With Severe Hemophilia A
Actual Study Start Date : November 23, 2015
Actual Primary Completion Date : August 5, 2018
Actual Study Completion Date : August 5, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hemophilia

Arm Intervention/treatment
Experimental: Pharmacokinetic (PK) evaluation of BAX 855
Participants will first undergo an initial pharmacokinetic (PK) assessment. Following the PK assessment participants will be randomized to one of 2 dosing regimens.
Biological: PEGylated Recombinant Factor VIII
Pharmacokinetic (PK) evaluation
Other Names:
  • BAX855
  • BAX 855

Experimental: FVIII trough target 1-3%
Standard treatment arm - PK-guided dosing schedule to achieve a Factor VIII (FVIII) trough of 1-3%
Biological: PEGylated Recombinant Factor VIII
Standard treatment
Other Names:
  • BAX 855
  • BAX855

Experimental: FVIII trough target 8-12%
Intensified treatment arm - PK-guided dosing schedule to achieve a Factor VIII (FVIII) trough of 8-12%
Biological: PEGylated Recombinant Factor VIII
Intensified treatment
Other Names:
  • BAX855
  • BAX 855




Primary Outcome Measures :
  1. Percentage of Participants With a Total Annualized Bleeding Rate (ABR) of Zero for Second Six Months [ Time Frame: Day 183 to Day 364 (6 months) ]
    Annualized bleeding rate was determined by dividing the number of bleeds by observation period in years.


Secondary Outcome Measures :
  1. Total Annualized Bleeding Rate for Second Six Months [ Time Frame: Day 183 to Day 364 (6 months) ]
    Annualized bleeding rate was determined by dividing the number of bleeds by observation period in years.

  2. Annualized Spontaneous Bleeding Rate for Second Six Months [ Time Frame: Day 183 to Day 364 (6 months) ]
    Annualized spontaneous bleeding rate was determined by dividing the number of spontaneous bleeds by observation period in years. A bleed was defined as spontaneous if it was not related to injury/trauma.

  3. Annualized Traumatic Bleeding Rate for Second Six Months [ Time Frame: Day 183 to Day 364 (6 months) ]
    Annualized traumatic bleeding rate was determined by dividing the number of traumatic bleeds by observation period in years. A bleed was defined as traumatic if it was related to injury/trauma.

  4. Annualized Joint Bleeding Rate (AJBR) for Second Six Months [ Time Frame: Day 183 to Day 364 (6 months) ]
    Annualized joint bleeding rate was determined by dividing the number of joint bleeds by observation period in years. An acute joint bleed include some or all of the following: 'aura', pain, swelling, warmth of the skin over the joint, decreased range of motion and difficulty in using the limb compared with baseline or loss of function.

  5. Total Weight-adjusted Consumption of BAX 855 [ Time Frame: From start of study treatment up to 12 months (completion or termination) ]
    Total weight-adjusted consumption of BAX 855 were reported.

  6. Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Number of Infusions [ Time Frame: 8 hours after study drug administration ]
    The participant or caregiver rated the overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and 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 and required more than 1 infusion for complete resolution and None: No improvement or condition worsens.

  7. Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution [ Time Frame: From start of study treatment up to bleed resolution (up to 12 months) ]
    The participant or caregiver rated the overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and 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 and required more than 1 infusion for complete resolution and None: No improvement or condition worsens.

  8. Treatment of Bleeding Episodes: Number of BAX 855 Infusions Per Bleeding Episode Required Until Bleed Resolution [ Time Frame: From start of study treatment up to 12 months (completion or termination) ]
    Infusions of BAX 855 that were required until bleed resolution were reported.

  9. Change From Baseline in Hemophilia Joint Health Score (HJHS)- Total Score [ Time Frame: Baseline, Month 12 ]
    HJHS was assessed based on the following components of the elbow, knee, and ankle joints: swelling, duration of swelling, muscle atrophy, crepitus on motion, flexion loss, extension loss, joint pain, and strength, together with an assessment of the global gait. The HJHS is a validated 11-item scoring tool based on radiologic and clinical evaluation, sensitive to detect early signs and minor changes. HJHS ranges from 0 to 124. Higher values in the HJHS represent worse situation for the participant.

  10. Number of Participants With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds [ Time Frame: Day 0 through discharge or 14 days post-surgery ]
    The participant or caregiver rated the overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and 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 and required more than 1 infusion for complete resolution and None: No improvement or condition worsens. Hemostatic efficacy was evaluated intra-operatively (from start to end of the procedure), post-operatively (from the end of procedure up to 24 h post procedure), and perioperatively (from the start of procedure to participant discharge from hospital or 14 days after completion of procedure; whichever was first).

  11. Blood Loss Per Participant in Case of Surgery [ Time Frame: Day 0 through discharge or 14 days post-surgery ]
    The intraoperative blood loss was measured by determining the volume of blood and fluid removal through suction into the collection container (waste box and/or cell saver) and the estimated blood loss into swabs and towels during the procedure, per the anesthesiologist's record. Postoperatively, blood loss was determined by the drainage volume collected, which mainly consisted of drainage fluid via vacuum or gravity drain, as applicable. In cases where no drain was present, blood loss was determined by the surgeon's clinical judgment, as applicable or entered as "not available". Blood loss was evaluated intra-operatively (from start to end of the procedure), post-operatively (from the end of procedure up to 24 h post procedure), and perioperatively (from the start of procedure to participant discharge from hospital or 14 days after completion of procedure; whichever was first).

  12. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: From start of study treatment up to 12 months (completion or termination) ]
    An AE was any unfavorable and unintended sign (an abnormal laboratory finding), symptom (rash, pain, discomfort, fever, dizziness, etc.), disease (peritonitis, bacteremia, etc.), or outcome of death temporally associated with the use of an investigational product (IP), whether or not considered causally related to the IP. A SAE was defined as an untoward medical occurrence that at any dose met one or more of the following criteria: outcome was fatal/results in death, life-threatening, required in-patient hospitalization or resulted in prolongation of an existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event that was not immediately life-threatening or resulted in death or required hospitalization but jeopardize the participant or required medical or surgical intervention to prevent any of the above outcomes.

  13. Number of Participants With Clinically Significant Changes in Vital Signs Reported as Treatment Related Adverse Events [ Time Frame: From start of study treatment up to 12 months (completion or termination) ]
    Vital signs included systolic and diastolic blood pressure, pulse rate, respiratory rate, body temperature.

  14. Number of Participants With Clinically Significant Changes in Clinical Laboratory Parameters Reported as Treatment Related Adverse Events [ Time Frame: From start of study treatment up to 12 months (completion or termination) ]
    Clinical laboratory assessments included clinical chemistry, hematology, lipid panel, genetics, T-cell, B-cell and NK cell (TBNK) and viral serology.

  15. Number of Participants With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein [ Time Frame: From start of study treatment up to 12 months (completion or termination) ]
    Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein were reported here.

  16. Change From Baseline in Physical Component Scores (PCS) of the Short Form-36 (SF-36) Health Survey [ Time Frame: Baseline, Month 12 (completion or termination) ]
    Short Form (36) Health Survey (SF-36) is a 36-item validated, generic health related quality of life (HR QoL) instrument. PCS is a summary scale of the dimensions physical functioning, role physical, bodily pain, and general health. The component score is normalized to a standard population. Scores range from 0 to 100 with higher scores representing better health. There is no total overall score; scoring is done for both sub-scores and summary scores.

  17. Area Under the Plasma Concentration of BAX 855 From Zero to Infinity (AUC0-inf) [ Time Frame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion ]
    Area under the plasma concentration versus time curve from time 0 to infinity of BAX 855 were reported.

  18. Incremental Recovery (IR) at Maximum Plasma Concentration (Cmax) of BAX 855 [ Time Frame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion ]
    IR at Cmax of BAX 855 were reported.

  19. Plasma Half-life (T1/2) of BAX 855 [ Time Frame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion ]
    T1/2 of BAX 855 in plasma were reported.

  20. Mean Residence Time (MRT) of BAX 855 [ Time Frame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion ]
    MRT of BAX 855 were reported.

  21. Maximum Plasma Concentration (Cmax) of BAX 855 [ Time Frame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion ]
    Cmax of BAX 855 were reported.

  22. Time to Maximum Concentration of BAX 855 in Plasma (Tmax) [ Time Frame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion ]
    Tmax of BAX 855 were reported.

  23. Total Body Clearance (CL) of BAX 855 [ Time Frame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion ]
    Total body clearance of BAX 855 from blood by the kidney were reported.

  24. Volume of Distribution at Steady State (Vss) [ Time Frame: Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion ]
    Volume of distribution was defined as the theoretical volume in which the total amount of drug was uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steadystate.

  25. Incremental Recovery (IR) Over Time [ Time Frame: Baseline, Month 3, 6, 7.5, 9, 10.5, 12 (Completion or termination) ]
    Incremental recovery was calculated by BAX 855 increment (IU/dL) / BAX 855 dose (IU/kg).



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:   12 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

INCLUSION CRITERIA:

  • Participants transitioning from another BAX 855 study who meet ALL of the following criteria are eligible for this study:

    1. Participant has completed the end of study visit of a BAX 855 study or is transitioning from the ongoing Baxalta Continuation Study 261302.
    2. Participant is either receiving on-demand treatment or prophylactic treatment with BAX 855 and had an Annual Bleed Rate (ABR) of ≥ 2 documented and treated during the past 12 months.
    3. Participant is human immunodeficiency virus negative (HIV-); or HIV+ with stable disease and CD4+ count ≥ 200 cells/mm^3, as confirmed by central laboratory.
    4. Participant is willing and able to comply with the requirements of the protocol.
  • Newly recruited participants (ie not transitioning from another BAX 855 study) including BAX855 naïve participants who meet ALL of the following criteria are eligible for this study:

    1. Participant has severe hemophilia A (FVIII clotting activity < 1%) as confirmed by central laboratory OR by historically documented FVIII clotting activity performed by a certified clinical laboratory, optionally supported by a FVIII gene mutation consistent with severe hemophilia A
    2. Participant has been previously treated with plasma-derived FVIII concentrates or recombinant FVIII for ≥ 150 documented exposure days (EDs)
    3. Participant is either receiving on-demand treatment or prophylactic treatment and had an annual bleeding rate of ≥ 2 documented and treated during the past 12 months.
    4. Participant has a Karnofsky performance score of ≥ 60 at screening
    5. Participant is HIV-; or HIV+ with stable disease and CD4+ count ≥ 200 cells/mm^3, as confirmed by central laboratory at screening
    6. Participant is hepatitis C virus negative (HCV-) by antibody (if positive, additional PCR testing will be performed), as confirmed by central laboratory at screening; or HCV+ with chronic stable hepatitis
    7. If female of childbearing potential, participant presents with a negative urine pregnancy test and agrees to employ adequate birth control measures for the duration of the study
    8. Participant is willing and able to comply with the requirements of the protocol.

EXCLUSION CRITERIA:

  • Participants transitioning from another BAX 855 study who meet ANY of the following criteria are not eligible for this study:

    1. Participant has developed a confirmed inhibitory antibody to FVIII with a titer of ≥ 0.6 BU using the Nijmegen modification of the Bethesda assay as determined at the central laboratory during the course of the previous BAX 855 study.
    2. Participant has been diagnosed with an acquired hemostatic defect other than hemophilia A.
    3. The participant's weight is < 35 kg or > 100 kg.
    4. Participant's platelet count is < 100,000/mL.
    5. Participant has an abnormal renal function (serum creatinine > 1.5 times the upper limit of normal).
    6. Participant has active hepatic disease with alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels ≥ 5 times the upper limit of normal.
    7. Participant is scheduled to receive a systemic immunomodulating drug (e.g. corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day, or α-interferon) other than anti-retroviral chemotherapy during the study.
    8. Participant has a clinically significant medical, psychiatric, or cognitive illness, or recreational drug/alcohol use that, in the opinion of the investigator, would affect participant's safety or compliance.
    9. Participant is planning to take part in any other clinical study during the course of the study.
    10. Participant is a member of the team conducting this study or is in a dependent relationship with one of the study team members. Dependent relationships include close relatives (ie, children, partner/spouse, siblings, parents) as well as employees of the investigator or site personnel conducting the study.

Newly recruited participants (ie not transitioning from another BAX 855 study) who meet ANY of the following criteria are not eligible for this study:

  1. Participant has detectable FVIII inhibitory antibodies (≥ 0.6 BU using the Nijmegen modification of the Bethesda assay) as confirmed by central laboratory at screening.
  2. Participant has a history of confirmed FVIII inhibitors with a titer ≥ 0.6 Bethesda Units (BU) (as determined by the Nijmegen modification of the Bethesda assay or the assay employed with the respective cut-off in the local laboratory) at any time prior to screening.
  3. Participant has been diagnosed with an inherited or acquired hemostatic defect other than hemophilia A (eg, qualitative platelet defect or von Willebrand's disease).
  4. The participant's weight is < 35 kg or > 100 kg.
  5. Participant's platelet count is < 100,000/mL.
  6. Participant has known hypersensitivity towards mouse or hamster proteins, PEG or Tween 80.
  7. Participant has severe chronic hepatic dysfunction [eg, ≥ 5 times upper limit of normal alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), as confirmed by central laboratory at screening, or a documented INR > 1.5].
  8. Participant has severe renal impairment (serum creatinine > 1.5 times the upper limit of normal).
  9. Participant has current or recent (< 30 days) use of other pegylated drugs prior to study participation or is scheduled to use such drugs during study participation.
  10. Participant is scheduled to receive during the course of the study, a systemic immunomodulating drug (e.g. corticosteroid agents at a dose equivalent to hydrocortisone greater than 10 mg/day, or α-interferon) other than anti-retroviral chemotherapy.
  11. Participant has participated in another clinical study involving an IP 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.
  12. Participant has a medical, psychiatric, or cognitive illness or recreational drug/alcohol use that, in the opinion of the investigator, would affect participant safety or compliance.
  13. Participant is a member of the team conducting this study or is in a dependent relationship with one of the study team members. Dependent relationships include close relatives (ie, children, partner/spouse, siblings, parents) as well as employees of the investigator or site personnel conducting the study.

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): NCT02585960


Locations
Show Show 83 study locations
Sponsors and Collaborators
Baxalta now part of Shire
Baxalta Innovations GmbH, now part of Shire
Investigators
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Study Director: Study Director Shire
  Study Documents (Full-Text)

Documents provided by Shire ( Baxalta now part of Shire ):
Study Protocol: Protocol  [PDF] January 13, 2015
Study Protocol: Amendment 1  [PDF] March 20, 2015
Study Protocol: Amendment 2  [PDF] May 12, 2015
Study Protocol: Amendment 3  [PDF] September 4, 2015
Study Protocol: Amendment 5  [PDF] October 18, 2016
Statistical Analysis Plan  [PDF] September 19, 2018

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Responsible Party: Baxalta now part of Shire
ClinicalTrials.gov Identifier: NCT02585960    
Other Study ID Numbers: 261303
2014-005477-37 ( EudraCT Number )
First Posted: October 26, 2015    Key Record Dates
Results First Posted: August 26, 2019
Last Update Posted: September 12, 2019
Last Verified: September 2019
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
Additional relevant MeSH terms:
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Hemophilia A
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Factor VIII
BAX 855
Coagulants