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ADVATE/ ADYNOVI Hemophilia A Outcome Database (AHEAD) (AHEAD)

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: NCT02078427
Recruitment Status : Recruiting
First Posted : March 5, 2014
Last Update Posted : May 8, 2019
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 the study is to document the natural history of hemophilia A disease and long-term outcomes in terms of effectiveness, safety and quality of life in participants receiving Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method (rAHF-PFM) or Antihemophilic Factor (Recombinant) - Pegylated (rAHF-PEG) in routine clinical practice

Condition or disease Intervention/treatment
Hemophilia A Biological: ADVATE Biological: ADYNOVI

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Study Type : Observational
Estimated Enrollment : 630 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: ADVATE/ ADYNOVI Hemophilia A Outcome Database
Actual Study Start Date : June 29, 2011
Estimated Primary Completion Date : January 15, 2025
Estimated Study Completion Date : January 15, 2025


Group/Cohort Intervention/treatment
rAHF-PFM
Participants treated with rAHF-PFM alone
Biological: ADVATE
Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method
Other Names:
  • octocog alfa
  • rAHF-PFM

rAHF-PEG
Participants treated with rAHF-PEG alone
Biological: ADYNOVI
Antihemophilic Factor (Recombinant) Pegylated
Other Names:
  • rurioctocog alfa pegol
  • rAHF-PEG

rAHF-PFM then rAHF-PEG
Participants treated with rAHF-PFM and subsequently switched to rAHF-PEG
Biological: ADVATE
Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method
Other Names:
  • octocog alfa
  • rAHF-PFM

Biological: ADYNOVI
Antihemophilic Factor (Recombinant) Pegylated
Other Names:
  • rurioctocog alfa pegol
  • rAHF-PEG




Primary Outcome Measures :
  1. Joint Health Outcomes - Assessed by Physical Exam Using Only the Pain, Bleeding, and Physical Exam Parameters of the Gilbert Scale [ Time Frame: Up to approximately 12 years ]
    The World Federation of Hemophilia developed a musculoskeletal evaluation system, commonly referred to as the Gilbert test, to measure hemophilia joint health status.The Gilbert test needs to be performed in the absence of acute bleed, acute pain, and acute inflammation into the evaluated joint. Four parameters are used in each Gilbert test: pain (score: 0-3), bleeding (score: 0-3), physical exam (score: 0-12), and X-ray evaluation (score: 0-13) Scores of 0, represent no pain, no bleeding, no physical exam issues, and/or no x-ray issues. Higher scores for each of these categories represents worsening conditions.


Secondary Outcome Measures :
  1. Annualized Bleed Rate, All Joints [ Time Frame: Annual/Interval visits:- Up to 8 years if rAHF-PFM alone- Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years- Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; and Termination visit ]
    The annualized bleed rate for all joints will be calculated per participant and summarized over the set of available participants with a minimum observation period of 90 days per treatment regimen.

  2. Annualized Bleed Rate, All Bleeds [ Time Frame: Annual/Interval visits:- Up to 8 years if rAHF-PFM alone- Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years- Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; and Termination visit ]
    The annualized bleed rate for all bleeds will be calculated per participant and summarized over the set of available participants.with a minimum observation period of 90 days per treatment regimen.

  3. Annualized bleed rate, pre-existing target joints at baseline [ Time Frame: Screening visit; Annual/Interval visits:- Up to 8 years if rAHF-PFM alone- Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years- Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; and Termination visit ]
    The annualized bleed rate for pre-existing target joints at baseline will be calculated per participant and summarized over the set of available participants with a minimum observation period of 90 days per treatment regimen.

  4. Incidence of New Target Joints [ Time Frame: Screening visit; Annual/Interval visits:- Up to 8 years if rAHF-PFM alone- Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years- Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; and Termination visit ]
    The incidence of new target joints will be calculated as the total number of new target joints in all participants divided by the total number of observation days.

  5. Status of joint health by X-ray by Pettersson scale [ Time Frame: Screening visit; Annual/Interval visits:- Up to 8 years if rAHF-PFM alone- Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years- Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; and Termination visit. ]
    The status of joint health by X-ray by Pettersson score will be summarized for each observational year.

  6. Status of Joint Health by Magnetic Resonance Imaging (MRI) Scoring System- Using The Lund Scoring System (LSS) [ Time Frame: Screening visit; Annual/Interval visits:- Up to 8 years if rAHF-PFM alone- Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years- Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; and Termination visit ]

    LSS score format= A(e:s:h). Sum of values for Subchondral Cyst (score: 1-6), irregularity/erosion of Subchondral Cortex (score: 1-4), and Chondral Destruction (score: 1-6) gives value for the A component of score. e, s, h components represent effusion/hemarthrosis, hypertrophic synovial, & hemosiderin deposition (score: 0-4 for each). Max. score is 16(4:4:4).

    Subchondral Cyst:

    • ≥1 bone
    • ≥2 bones
    • >3 cysts in ≥1 bone
    • >3 cysts ≥2 bones
    • Largest size >4 mm: ≥1 bone
    • Largest size >4 mm: ≥2 bones

    Subchondral Cortex

    • ≥1 bone
    • ≥2 bones
    • Involve > half joint surface: ≥1 bone
    • Involve > half of joint surface: ≥2 bones

    Chondral Destruction

    • ≥1 bone
    • ≥2 bones
    • Full thickness defect (FTD): ≥1 bone
    • FTD: ≥2 bones
    • FTD involves >1/3 of joint surface: ≥1 bone
    • FTD involves >1/3 of joint surface: ≥2 bones

    Effusion/hemarthrosis (e): Hypertrophic synovial (s): Hemosiderin (h): (0-4 for each):

    • 0 absent
    • 1 equivocal
    • 2 small
    • 3 moderate
    • 4 large

  7. Status of joint health using the Hemophilia Joint Health Score (HJHS) [ Time Frame: Screening visit; Annual/Interval visits:- Up to 8 years if rAHF-PFM alone- Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years- Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; and Termination visit ]

    The International Prophylaxis Study Group (IPSG) developed a scoring system for musculoskeletal evaluation, the HJHS, optimized for use in children with no or minimal joint disease.

    The HJHS includes the following parameters: swelling, duration of swelling, muscle atrophy, joint pain, crepitus on motion, flexion loss, extension loss, strength and global gait.


  8. Overall effectiveness assessment for prophylaxis therapy [ Time Frame: Annual/Interval visits:- Up to 8 years if rAHF-PFM alone;- Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years;- Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; and Termination visit ]
    • Excellent: Same or lower breakthrough bleed rate (BBR) within last 12 months (M) compared with prior prophylaxis; if participant did not receive prior prophylaxis with rAHF-PFM, rAHF-PEG or other Factor VIII (FVIII), same or better than expected outcome according to investigator's expectation
    • Good: Minor increase in BBR within last 12M compared with prior prophylaxis; if participant did not receive prophylaxis with rAHF-PFM, rAHF-PEG or other FVIII, slightly less than expected outcome according to investigator's expectation
    • Fair: Moderate increase in BBR in last 12M compared with prior prophylaxis; if participant did not receive prophylaxis with rAHF-PFM, rAHF-PEG or other FVIII, somewhat less than expected outcome according to investigator's expectation
    • Poor: Significant increase in BBR in the 12M compared with prior prophylaxis; if participant did not receive prophylaxis with rAHF-PFM, rAHF-PEG or other FVIII, little to no benefit according to investigator's expectation

  9. Compliance with the dosing prescribed and its relationship with effectiveness [ Time Frame: Annual/Interval visits:- Up to 8 years if rAHF-PFM alone;- Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years;- Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; and Termination visit ]
    Evaluation of patients´ compliance to prescribed prophylactic treatment will be performed by the treating physician. Compliance will be categorized according to a 4-point table (Highly compliant, Fairly compliant, Moderately compliant, Poorly compliant)

  10. Overall effectiveness assessment for on-demand treatment [ Time Frame: Annual/Interval visits: - Up to 8 years if rAHF-PFM alone - Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years - Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; and Termination visit ]
    • Excellent: Bleed episodes typically respond to same or fewer number of infusion and same or lower dose as compared with previous on-demand treatment or investigator's expectation
    • Good: Most bleed episodes typically respond to same number of infusion and dose but some require more infusions or higher dose as compared with previous on-demand treatment or investigator's expectation
    • Fair: Bleed episodes typically require more infusions and/or higher dose than expected as compared with previous on-demand treatment or investigator's expectation
    • Poor: Bleed episodes routinely fail to respond to same number of infusion and dose and require additional or different factor concentrate for hemostatic control as compared with previous on-demand treatment or investigator's expectation

  11. Global effectiveness assessment for on-demand treatment [ Time Frame: Annual/Interval visits: - Up to 8 years if rAHF-PFM alone - Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years - Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; and Termination visit ]
    • Excellent: Full relief of pain and cessation of bleeding as evidenced by objective signs (e.g., swelling, tenderness, irritability, inconsolability, and decreased range of motion in the case of musculoskeletal hemorrhage) within approximately 8 hours of 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 within approximately 8 hours after the infusion. Possibly requires more than 1 infusion for complete resolution.
    • Fair: Probable or slight relief of pain and slight improvement in signs of bleeding within approximately 8 hours after the infusion. Requires more than 1 infusion for complete resolution.
    • Poor: No improvement or condition worsens.

  12. Number of rAHF-PFM or rAHF-PEG units required for bleed cessation [ Time Frame: Annual/Interval visits: - Up to 8 years if rAHF-PFM alone - Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years - Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; and Termination visit ]
    Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method (rAHF-PFM) Antihemophilic Factor (Recombinant) - Pegylated (rAHF-PEG)

  13. Number of rAHF-PFM or rAHF-PEG infusions required for bleed cessation [ Time Frame: Annual/Interval visits: - Up to 8 years if rAHF-PFM alone - Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years - Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; and Termination visit ]
    Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method (rAHF-PFM) Antihemophilic Factor (Recombinant) - Pegylated (rAHF-PEG)

  14. Incidence of target joint intervention, including surgery, radiosynovectomy, and chemosynovectomy [ Time Frame: Screening visit; Annual/Interval visits: - Up to 8 years if rAHF-PFM alone - Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years - Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; and Termination visit ]
  15. Incidence of pseudo tumor development [ Time Frame: Screening visit; Annual/Interval visits: - Up to 8 years if rAHF-PFM alone - Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years - Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; Termination visit ]
  16. Quality of Life: HAL questionnaire - for adult patients [ Time Frame: Enrollment visit; Screening visit; Annual/Interval visits: - Up to 8 years if rAHF-PFM alone - Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years - Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; Termination visit ]
    The the lHAL measures activities involving the upper extremities, basic activities involving ower extremities and complex activities involving the lower extremities as well as an overall physical activity score for adults.

  17. Quality of Life: SF-12v2 questionnaire - for adult patients [ Time Frame: Enrollment visit; Screening visit; Annual/Interval visits: - Up to 8 years if rAHF-PFM alone - Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years - Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; Termination visit ]
    The SF-12v2 measures generic health-related quality of life for adults.

  18. Quality of Life: EQ-5D questionnaire - for adult patients [ Time Frame: Enrollment visit;Screening visit; Annual/Interval visits: - Up to 8 years if rAHF-PFM alone - Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years - Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; Termination visit ]
    The EQ-5D measures health utility in adult participants.

  19. Quality of Life: PedHAL questionnaire - for pediatric patients [ Time Frame: Enrollment visit; Screening visit; Annual/Interval visits: - Up to 8 years if rAHF-PFM alone - Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years - Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; Termination visit ]

    The PedHAL measures activities involving the upper extremities, basic activities involving the lower extremities and complex activities involving the lower extremities as well as an overall physical activity score for children.

    For participants 4-13 years of age:

    - PedHAL (parent version)

    For participants 14-17 years of age:

    - PedHAL (child version)


  20. Quality of Life: SF-10 questionnaire - for pediatric patients [ Time Frame: Enrollment visit; Screening visit; Annual/Interval visits: - Up to 8 years if rAHF-PFM alone - Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years - Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; Termination visit ]
    The SF-10 measures generic health-related quality of life for children and is parent-completed.

  21. Quality of Life: EQ-5D (14 and up) questionnaire - for pediatric patients [ Time Frame: Enrollment visit; Screening visit; Annual/Interval visits: - Up to 8 years if rAHF-PFM alone - Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years - Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; Termination visit ]
    The EQ-5D measures health utility in subjects aged 14 and up.

  22. Chronic pain associated with hemophilia, as measured over a period of 4 weeks on an annual basis, using the visual analog scale (VAS) [ Time Frame: Enrollment visit; Screening visit; Annual/Interval visits: - Up to 8 years if rAHF-PFM alone - Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years - Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; Termination visit ]

    The VAS assesses the pain using a scale of 0 (no pain) to 10 (unbearable pain).

    During screening visit and on an annual basis, the investigators shall ask participants to rate the average level of chronic pain associated with hemophilia over the period of 4 weeks prior to visit date using the VAS.


  23. Acute pain associated with hemophilia, as measured with individual bleeding episodes, using the visual analog scale (VAS) [ Time Frame: Enrollment visit; Screening visit; Annual/Interval visits: - Up to 8 years if rAHF-PFM alone - Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years - Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; Termination visit ]

    The VAS assesses the pain using a scale of 0 (no pain) to 10 (unbearable pain).

    Participants will be asked to provide ratings on level of acute pain associated with each bleeding episode using the VAS. The VAS scores will be recorded in the participant diary.


  24. Number of days lost from school or work due to bleeding episodes [ Time Frame: Enrollment visit; Screening visit; Annual/Interval visits: - Up to 8 years if rAHF-PFM alone - Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years - Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; Termination visit ]
  25. Modalities of switching from a standard FVIII product to rAHF-PEG - 1 [ Time Frame: Enrollment visit; Screening visit; Annual/Interval visits: - Up to 8 years if rAHF-PFM alone - Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years - Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; Termination visit ]
    Difference in number of weekly prophylactic infusions between previous regimen and rAHF-PEG

  26. Modalities of switching from a standard FVIII product to rAHF-PEG - 2 [ Time Frame: Enrollment visit; Screening visit; Annual/Interval visits: - Up to 8 years if rAHF-PFM alone - Up to 8 years if rAHF-PEG alone with minimum follow up of 4 years - Up to approx. 12 years rAHF-PFM and switched to rAHF-PEG; Termination visit ]
    Difference in number of weekly doses between previous regimen and rAHFPEG

  27. Incidence of Inhibitors in Previously Treated Patients (PTPs) with Factor VIII (FVIII) Levels Lesser than (<)1%, Lesser Than or Equal to (<=) 2%, and <= 5% without history of inhibitor [ Time Frame: Throughout the study period of up to approximately: 8 years (rAHF-PFM alone), or 12 years (rAHF-PEG alone or after receiving rAHF-PFM) ]
  28. Incidence of Inhibitors in Previously Treated Patients (PTPs) with Factor VIII (FVIII) Levels <1%, <=2%, and <= 5% with history of inhibitor [ Time Frame: Throughout the study period of up to approximately: 8 years (rAHF-PFM alone), or 12 years (rAHF-PEG alone or after receiving rAHF-PFM) ]
  29. Incidence of Inhibitors in Previously Untreated Patient (PUPs) and Minimally Treated Patients (MTPs) with Factor VIII (FVIII) Levels <1%, <=2%, and <= 5% [ Time Frame: Throughout the study period of up to approximately: 8 years (rAHF-PFM alone), or 12 years (rAHF-PEG alone or after receiving rAHF-PFM) ]
  30. Incidence of therapy-related serious adverse events [ Time Frame: Throughout the study period of up to approximately: 8 years (rAHF-PFM alone), or 12 years (rAHF-PEG alone or after receiving rAHF-PFM) ]
  31. Incidence of therapy-related non-serious adverse events [ Time Frame: Throughout the study period of up to approximately: 8 years (rAHF-PFM alone), or 12 years (rAHF-PEG alone or after receiving rAHF-PFM) ]
  32. Incidence of inhibitors after switching to rAHF-PEG [ Time Frame: Throughout the study period of up to approximately: 8 years (rAHF-PFM alone), or 12 years (rAHF-PEG alone or after receiving rAHF-PFM) ]
    Incidence of inhibitors after switching to rAHF-PEG in the same subgroups of patients



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:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
The study population will include male and female participants of any race and age who have a diagnosis of hemophilia A (Factor VIII (FVIII) =5%). Participants must have been prescribed rAHF-PFM or rAHF-PEG for the management of hemophilia A by the treating physician prior to the decision to enroll in the study.
Criteria

Inclusion Criteria:

  • Participant has hemophilia A {FVIII lesser than or equal to (<=)5%}
  • Participant is prescribed Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method (rAHF-PFM) or Antihemophilic Factor (Recombinant) - Pegylated (rAHF-PEG) by the treating physician
  • Participant or participant's legally authorized representative provides informed consent

Exclusion Criteria:

  • Participant has known hypersensitivity to the active substance or any of the excipients
  • Participant has known allergic reaction to mouse or hamster proteins
  • Participant has participated in another clinical study involving an investigational product (IP) or device within 30 days prior to study enrollment or is scheduled to participate in another clinical study involving another FVIII concentrate or device during the course of this 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): NCT02078427


Contacts
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Contact: Shire Contact +1 866 842 5335 ClinicalTransparency@shire.com

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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

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Responsible Party: Baxalta now part of Shire
ClinicalTrials.gov Identifier: NCT02078427     History of Changes
Other Study ID Numbers: 061001
First Posted: March 5, 2014    Key Record Dates
Last Update Posted: May 8, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

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
Coagulants