ADVATE/ ADYNOVI Hemophilia A Outcome Database (AHEAD)

Study Overview
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Brief Summary
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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

Official Title
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ADVATE/ ADYNOVI Hemophilia A Outcome Database

Conditions
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Hemophilia A

Intervention / Treatment
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* Biological: ADVATE
* Biological: ADYNOVI


Participation Criteria
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Eligibility Criteria
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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
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| rAHF-PFM<br>Participants treated with rAHF-PFM alone | Biological: ADVATE<br>* Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method<br>* Other names: rAHF-PFM;|
| rAHF-PEG<br>Participants treated with rAHF-PEG alone | Biological: ADYNOVI<br>* Antihemophilic Factor (Recombinant) Pegylated<br>* Other names: rAHF-PEG;|
| rAHF-PFM then rAHF-PEG<br>Participants treated with rAHF-PFM and subsequently switched to rAHF-PEG | Biological: ADVATE<br>* Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method<br>* Other names: rAHF-PFM;Biological: ADYNOVI<br>* Antihemophilic Factor (Recombinant) Pegylated<br>* Other names: rAHF-PEG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Joint Health Outcomes - Assessed by Physical Exam Using Only the Pain, Bleeding, and Physical Exam Parameters of the Gilbert Scale | 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. | Up to approximately 12 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized Bleed Rate, All Joints | 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. | 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 | 
| Annualized Bleed Rate, All Bleeds | 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. | 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 | 
| Annualized bleed rate, pre-existing target joints at baseline | 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. | 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 | 
| Incidence of New Target Joints | 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. | 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 | 
| Status of joint health by X-ray by Pettersson scale | The status of joint health by X-ray by Pettersson score will be summarized for each observational year. | 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. | 
| Status of Joint Health by Magnetic Resonance Imaging (MRI) Scoring System- Using The Lund Scoring System (LSS) | 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 | 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 | 
| Status of joint health using the Hemophilia Joint Health Score (HJHS) | 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. | 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 | 
| Overall effectiveness assessment for prophylaxis therapy | 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 | 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 | 
| Compliance with the dosing prescribed and its relationship with effectiveness | 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) | 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 | 
| Overall effectiveness assessment for on-demand treatment | 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 | 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 | 
| Global effectiveness assessment for on-demand treatment | 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. | 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 | 
| Number of rAHF-PFM or rAHF-PEG units required for bleed cessation | Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method (rAHF-PFM) Antihemophilic Factor (Recombinant) - Pegylated (rAHF-PEG) | 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 | 
| Number of rAHF-PFM or rAHF-PEG infusions required for bleed cessation | Antihemophilic Factor (Recombinant) - Plasma/Albumin Free Method (rAHF-PFM) Antihemophilic Factor (Recombinant) - Pegylated (rAHF-PEG) | 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 | 
| Incidence of target joint intervention, including surgery, radiosynovectomy, and chemosynovectomy |  | 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 | 
| Incidence of pseudo tumor development |  | 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 | 
| Quality of Life: HAL questionnaire - for adult patients | 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. | 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 | 
| Quality of Life: SF-12v2 questionnaire - for adult patients | The SF-12v2 measures generic health-related quality of life for adults. | 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 | 
| Quality of Life: EQ-5D questionnaire - for adult patients | The EQ-5D measures health utility in adult participants. | 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 | 
| Quality of Life: PedHAL questionnaire - for pediatric patients | 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) | 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 | 
| Quality of Life: SF-10 questionnaire - for pediatric patients | The SF-10 measures generic health-related quality of life for children and is parent-completed. | 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 | 
| Quality of Life: EQ-5D (14 and up) questionnaire - for pediatric patients | The EQ-5D measures health utility in subjects aged 14 and up. | 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 | 
| Chronic pain associated with hemophilia, as measured over a period of 4 weeks on an annual basis, using the visual analog scale (VAS) | 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. | 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 | 
| Acute pain associated with hemophilia, as measured with individual bleeding episodes, using the visual analog scale (VAS) | 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. | 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 | 
| Number of days lost from school or work due to bleeding episodes |  | 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 | 
| Modalities of switching from a standard FVIII product to rAHF-PEG - 1 | Difference in number of weekly prophylactic infusions between previous regimen and rAHF-PEG | 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 | 
| Modalities of switching from a standard FVIII product to rAHF-PEG - 2 | Difference in number of weekly doses between previous regimen and rAHFPEG | 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 | 
| 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 |  | 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 in Previously Treated Patients (PTPs) with Factor VIII (FVIII) Levels <1%, <=2%, and <= 5% with history of inhibitor |  | 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 in Previously Untreated Patient (PUPs) and Minimally Treated Patients (MTPs) with Factor VIII (FVIII) Levels <1%, <=2%, and <= 5% |  | 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 therapy-related serious adverse events |  | 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 therapy-related non-serious adverse events |  | 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 | Incidence of inhibitors after switching to rAHF-PEG in the same subgroups of patients | Throughout the study period of up to approximately: 8 years (rAHF-PFM alone), or 12 years (rAHF-PEG alone or after receiving rAHF-PFM) |