PHYSICAL ACTIVITY AND FVIII CLEARANCE: RELEVANCE FOR PERSONALIZED THERAPY IN SEVERE HAEMOPHILIA A (PHYSEMO)

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Subjects With Severe Haemophilia A Validation Study of a cOmputer Pharmacokinetic Tool to assIst in the Follow up Care of haeMophilia A Patients Joint Status in Subjects With Severe Hemophilia A in Relation to Different Treatment Regimens Safety Study of Alphanate in Previously Treated Patients With Severe Hemophilia A Treatment of Hemophilia A Patients With FVIII Inhibitors Comparison of Prophylaxis and On-demand Treatment in Children With Moderate to Severe Hemophilia A An Open Label Study to Determine the Safety and Efficacy of Replacement Factor VIII Protein (Known as rFVIIIFc) in Untreated Males With Severe Hemophilia A Assessment of the Risk of Inhibitor Formation in Previously Treated Patients With Severe Hemophilia A Efficacy and Safety of ADVATE Standard Prophylaxis to Hemophilia A Study to Evaluate the Efficacy and Safety of Valoctocogene Roxaparvovec, With Prophylactic Steroids in Hemophilia A National Study of a Pharmacokinetic-Focused Educational Package for Patients With Severe Haemophilia A Gene Therapy Trial for Platelet Derived Factor VIII Production in Hemophilia A Drug Use Investigation of Kovaltry in Hemophilia A Patients Safety, Immunogenicity and Hemostatic Efficacy of PEGylated Recombinant FVIII (BAX 855) in Previously Untreated Patients (PUPs) < 6 Years of Age With Severe Hemophilia A 2-cohort Study of Adult Patients With Severe Hemophilia A in Greece Study of Emicizumab Prophylaxis in Participants With Hemophilia A With or Without Inhibitors Undergoing Minor Surgical Procedures Efficacy, Safety, and Pharmacokinetic Study of Prophylactic Emicizumab Versus No Prophylaxis in Hemophilia A Participants Individually Tailored Prophylaxis in Patients With Severe Hemophilia A Single-Arm Study To Evaluate The Efficacy and Safety of Valoctocogene Roxaparvovec in Hemophilia A Patients Retrospective Chart Review to Evaluate Safety and Tolerability of ADVATE Among Previously Untreated Patients in China With Moderate to Severe Hemophilia A Comparison of 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Secondary Prophylaxis vs On-demand Therapy With Kogenate Bayer in Patients With Severe Haemophilia A.” Observational Study Describing the Usual Clinical Practice Use of NovoSeven® in the Home Treatment of Joint Bleeds in Patients With Haemophilia A or B and Inhibitors Thrombin Generation Numerical Models Validation in Haemophilic Case Efficacy and Safety Study of a Recombinant Protein-Free Manufactured Factor VIII (rAHF-PFM) in Previously Untreated Hemophilia A Patients Efficacy and Safety Study of a Recombinant and Protein-Free Factor VIII (rAHF-PFM) in Pediatric Patients in Canada With Hemophilia A – A Continuation of Baxter Study 060101 Study of a pd vWF/FVIII, Biostate®, in Subjects With Haemophilia A Phenotypic Heterogeneity in Hemophilia A: An Investigation of the Role of Platelet Function Study of Pharmacokinetics, Efficacy, and Safety of a Recombinant and Protein-Free Factor VIII (rAHF-PFM) in Pediatric Patients With Hemophilia A Study of Pharmacokinetics, Efficacy and Safety of a Recombinant and Protein-Free Factor VIII (rAHF-PFM) in Hemophilia A Patients – A Continuation of Clinical Study 069901 Study to Test the Safety and How Well Patients With Severe Hemophilia A Respond to Treatment With BAY 2599023 (DTX 201), a Drug Therapy That Delivers a Healthy Version of the Defective Factor VIII Gene Into the Nucleus of Liver Cells Using an Altered, Non-infectious Virus (AAV) as a “Shuttle”. A Trial Investigating Safety and Efficacy of Treatment With BAY94-9027 in Severe Hemophilia A Joint Health Study Study Evaluating Safety And Efficacy Of Moroctocog Alfa (AF-CC) In Previously Treated Hemophilia A Patients A Clinical Trial to Evaluate Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants Without Inhibitors UK – EHL Outcomes Registry Study to Establish Bioequivalence of ReFacto AF (BDDrFVIII) With Advate (FLrFVIII) in Hemophilia A Evaluation of Long-term Safety of ADYNOVI/ADYNOVATE (Antihaemophilic Factor [Recombinant] PEGylated, Rurioctocog Alfa Pegol) in Patients With Haemophilia A – An ADYNOVI/ADYNOVATE Post-Authorisation Safety Study (PASS) Platelet Function in Patients With Hemophilia A Study to Learn More About the Physical Activity Level of Patients Suffering From Hemophilia A Treated With Damoctocog Alfa Pegol (LIFE ACTIVE Study) Pharmacokinetic Characterization of the Hemophilia A Population in Spain Using myPKFiT® Impact of Conservative Treatment by Custom-made Orthoses in Patients With Haemophilic Ankle Arthropathy Pharmacokinetics, Efficacy and Safety Study of IMMUNATE SD (Human Plasma-Derived Coagulation Factor VIII Concentrate) in Hemophilia A Patients Characterization of Laboratory Response to DDAVP in Adult Hemophilia A Carriers Immune Tolerance Induction in Haemophilia A Patients Using Wilate or Nuwiq Combination Therapy of Low Doses of rFVIIa and FEIBA for Severe Hemophilia A Patients With an Inhibitor to Factor VIII Dose Confirmation Trial of AAV5-hFIXco-Padua Effects of Emicizumab vs. Factor VIII Prophylaxis on Joint and Bone Health in Severe Hemophilia A Patient Functioning and Well-being, Economic, and Clinical Impact of Hemophilia A and Its Treatment Web Accessible Population Pharmacokinetics Service – Hemophilia: Sources of Variability A Study Following People With Haemophilia A and B, With or Without Inhibitors, When on Usual Treatment (Explorer™6) Management of Health-Related QoL Impairment, Including Pain, Depression and Anxiety, in People With Haemophilia A and B The Dynamic Interplay Between Bleeding Phenotype and Baseline Factor Level in Moderate and Mild Hemophilia A and B RIXUBIS Drug Use-Result Survey (Japan) A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients With Inhibitors Evaluating Effectiveness and Long Term Safety of Damoctocog Alfa Pegol in Patients, Who Have Been Diagnosed With Hemophilia A Extended Half Life Factor (EHF) Products For Heavy Menstrual Bleeding in Hemophilia Carriers Study Evaluating ReFacto® in Hemophilia A Undergoing Major Surgery A Non-interventional Retrospective Study of the Current Treatment Practice in European Haemophilia Care BAX 326 Pediatric Study Recombinant Factor VIIa BI (rFVIIa BI) Treatment of Acute Bleeding Episodes Per an On-demand Regimen A Phase 1 Study of an Investigational Drug, ALN-AT3SC, in Healthy Volunteers and Hemophilia A or B Patients A Study of a Long-Acting r-Factor 7a (Factor VIIa) in Adult Men With Hemophilia A or B Females With Severe or Moderate Hemophilia A or B: an International Multi-center Study Females With Severe or Moderate Hemophilia A or B: A Multi-Center Study Socialization of Adult Men With Congenital Hemophilia A or B Study of Prophylaxis, ACtivity and Effectiveness (SPACE) in Hemophilia Patients Currently Treated With ADVATE or RIXUBIS An Observational Study to Evaluate Physical Activity, Bleeding Incidence and Health Related Quality of Life, in Participants With Haemophilia A Without Inhibitors Receiving Standard of Care Treatment Inhibitor Development in Patients With Hemophilia A Undergoing Surgery Study of the Efficacy and Safety PF-06741086 in Adult and Teenage Patients With Severe Hemophilia A or B Post-marketing Surveillance (Use Result Surveillance) With Refixia® Study Evaluating of Recombinant Human Factor IX (BeneFIX) and a New Formulation of BeneFIX (rFIX-R) in Moderate to Severe Hemophilia B A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients Without Inhibitors Phase I/II Study of Monoclonal Factor IX Concentrate for Factor IX Deficiency The Effectiveness of Recombinant Fusion Protein Linking Coagulation Factor IX With Recombinant Albumin (rIX-FP) in Severe Hemophilia B Patients Switching From Previous Factor IX Treatment The Safety and Tolerability of SerpinPC in Healthy Men and in Men With Severe Blood Disorders (Haemophilia A and B) IMMUNINE Pre-Treatment Study Efficacy and Safety of NNC-0156-0000-0009 During Surgical Procedures in Subjects With Haemophilia B Study of Ataluren (PTC124®) in Hemophilia A and B Safety of 40K Pegylated Recombinant Factor IX in Non-Bleeding Patients With Haemophilia B Fc factOrs and Real-World hemophiliA Patient-ReporteD Outcomes Bridging Hemophilia B Experiences, Results and Opportunities Into Solutions (B-HERO-S) Study Evaluating Approach to Treatment of Haemophilia A and B in Spain Global Epidemiologic Study of Preexisting Immunity to AAV in Adults With Severe Hemophilia Safety and Efficacy of Nonacog Beta Pegol (N9-GP) in Previously Untreated Patients With Haemophilia B Ascending Dose Study of Genome Editing by Zinc Finger Nuclease Therapeutic SB-FIX in Subjects With Severe Hemophilia B Safety and Efficacy of NNC-0156-0000-0009 After Long-Term Exposure in Patients With Haemophilia B: An Extension to Trials NN7999-3747 and NN7999-3773 Study Evaluating rFIX; BeneFIX® in Hemophilia B A Trial Comparing Nonacog Beta Pegol (N9-GP) and ALPROLIX® in Patients With Haemophilia B Tissue Factor Pathway Inhibitor (TFPI) and Haemorrhagic Manifestations in Haemophilia A and B Patients Safety and Pharmacokinetic Study of a Recombinant Coagulation Factor IX Albumin Fusion Protein in Subjects With Hemophilia B Long-term Safety and Efficacy Study of SPK-9001 in Individuals With Hemophilia B BAX 326 (rFIX) Continuation Study Nonacog Alfa Prophylaxis And Treatment Of Bleeding Episodes In Previously Treated Patients With Hemophelia B A Factor IX Gene Therapy Study (FIX-GT) Mutation p.Ile112Thr : Discrepancy Between Factor IX Level and Bleeding Phenotype LTFU for Gene Transfer Subjects With Hemophilia B A Phase 1/2 Study of SHP648, an Adeno-Associated Viral Vector for Gene Transfer in Hemophilia B Subjects Adverse Event Data Collection From External Registries on Nonacog Beta Pegol Safety and Efficacy of NNC-0156-0000-0009 in Haemophilia B Patients Lentiviral FIX Gene Therapy An Open Study to Investigate the Safety and Efficacy of Replenine®-VF in Severe Haemophilia B Patients Study to Describe the Allergic Reactions to Factor IX in Patients With Hemophilia B A Study to Evaluate the Real-world Usage and Effectiveness of Elocta and Alprolix in Patients With Haemophilia A or B A Long-Term Follow-Up Study of Haemophilia B Patients Who Have Undergone Gene Therapy A Study to Evaluate the Efficacy and Safety of Factor IX Gene Therapy With PF-06838435 in Adult Males With Moderately Severe to Severe Hemophilia B Long-Term Safety, Tolerability, and Efficacy of DTX101 (AAVrh10FIX) in Adults With Moderate/Severe to Severe Hemophilia B Post-Marketing Surveillance (Usage Results Study) of RIXUBIS in Adult and Pediatric Patients With Haemophilia B in South Korea Evaluation of a Recombinant Factor IX Product, APVO101, in Previously-Treated Pediatric Patients With Hemophilia B Understanding Hemophilia A and B Drug Dosage Administration Patterns Study of Recombinant Factor IX Product, IB1001, in Previously Treated Subjects With Hemophilia B Phase I/IIa Study of FIXFc in Hemophilia B Patients Safety, Efficacy and Pharmacokinetics of NNC-0156-0000-0009 in Previously Treated Children With Haemophilia B. A Study to Investigate the Safety and Efficacy of Replenine®-VF in Haemophilia B Patients Undergoing Major Surgery. HOPE-B: Trial of AMT-061 in Severe or Moderately Severe Hemophilia B Patients Long-Term Safety and Efficacy of rFIXFc in the Prevention and Treatment of Bleeding Episodes in Previously Treated Participants With Hemophilia B Study Evaluating Allergic Reactions To Benefix In Hemophilia B Patients A Safety and Efficacy Extension Study of a Recombinant Fusion Protein Linking Coagulation Factor IX With Albumin (rIX-FP) in Patients With Hemophilia B Study to Determine the Safety and Efficacy of rFIXFc in Untreated Males With Severe Hemophilia B Safety and Dose Finding Study of DTX101 (AAVrh10FIX) in Adults With Moderate/Severe to Severe Hemophilia B Open-Label Single Ascending Dose of Adeno-associated Virus Serotype 8 Factor IX Gene Therapy in Adults With Hemophilia B Prospective Registry of European Hemophilia B Patients Receiving BeneFIX® for Usual Use A Safety, Efficacy and Pharmacokinetics Study of a Recombinant Fusion Protein Linking Coagulation Factor IX With Albumin (rIX-FP) in Children With Hemophilia B Study of Recombinant Factor IX Product, IB1001, in Subjects With Hemophilia B A Study to Evaluate the Real-world Effectiveness and Usage of Alprolix in Patients With Haemophilia B in France An International Study to Evaluate the Real-world Effectiveness and Usage of Alprolix in Patients With Haemophilia B Study Evaluating BeneFIX in Patients With Haemophilia B, Previously Treated With Plasma Derived Factor IX A Gene Therapy Study for Hemophilia B A Safety and Efficacy Study of a Recombinant Fusion Protein Linking Coagulation Factor IX With Albumin (rIX-FP) in Patients With Hemophilia B A Study Following Males With Haemophilia B on Prophylaxis With Refixia/REBINYN A Safety and Efficacy Study of a Recombinant Factor IX in Patients With Severe Hemophilia B Gene Therapy for Chinese Hemophilia B BeneFIX Drug Use Results Survey [All-Case Surveillance] Safety of a New Type of Treatment Called Gene Transfer for the Treatment of Severe Hemophilia B Treatment Patterns And Outcomes In Patients Treated With Benefix Or Refacto/Refacto AF – A Swedish Cohort Study Hemophilia B Gene Therapy With AAV8 Vector Dose-Escalation Study Of A Self Complementary Adeno-Associated Viral Vector For Gene Transfer in Hemophilia B Study of Recombinant Factor IX Fc Fusion Protein (rFIXFc) in Participants With Hemophilia B Post Marketing Observational Study of Reformulated BeneFIX Study of Recombinant Factor IX Product, IB1001, in Previously Treated Pediatric Subjects With Hemophilia B Study of Next-Generation Recombinant Factor IX Variant in Adult Subjects With Hemophilia B An Open-Label, Single Dose Pharmacokinetic Study of Benefix (Recombinant Factor IX) in Male Chinese Subjects With Hemophilia B A Study to Investigate the Safety and Efficacy of Replenine®-VF in Haemophilia B Patients Under the Age of 6 Years Study of Recombinant Coagulation Factor IX Fc Fusion Protein, BIIB029, in Previously Treated Pediatric Participants With Hemophilia B An Open-study to Investigate the Safety and Efficacy of Replenine®-VF in Haemophilia B Subjects Undergoing Surgery Post Marketing Surveillance To Observe Safety and Efficacy Of BeneFIX In Patients With Hemophilia B BAX 326 Surgery Study in Hemophilia B Patients Registry For Patients Treated With BeneFix In Usual Care Setting In Germany Six Month lead-in Study to Evaluate Prospective Efficacy and Safety Data of Current FIX Prophylaxis Replacement Therapy in Adult Hemophilia B Subjects (FIX:C≤2%) or Current FVIII Prophylaxis Replacement Therapy in Adult Hemophilia A Subjects (FVIII:C≤1%) Trial of AAV5-hFIX in Severe or Moderately Severe Hemophilia B Study Comparing On-Demand Treatment With Two Prophylaxis Regimens Of BeneFIX In Patients With Severe Hemophilia B Study Evaluating On-Demand Treatment With BeneFIX In Chinese Subjects Study Evaluating rFIX; BeneFIX in Severe Hemophilia B Study To Compare On-Demand Treatment To A Prophylaxis Regimen Of BeneFIX In Subjects With Moderately Severe to Severe Hemophilia B Dose-escalation Study to Investigate the Safety, PK, and PD of ISU304/CB2679d in Hemophilia B Patients Post Marketing Study in Haemophilia B Patients Using Nonafact® (Human Coagulation Factor IX) A Study to Compare the Pharmacokinetics and Safety of Replenine®-VF, Replenine® or Other Factor IX in Haemophilia B Efficacy and Safety of AlphaNine Versus BeneFIX in Patients With Severe Hereditary Haemophilia B Study Evaluating BENEFIX in Previously Treated Patients With Hemophilia B Safety and Efficacy of Benefix in Patients With Hemophilia B in Usual Care Settings in China

Brief Title

PHYSICAL ACTIVITY AND FVIII CLEARANCE: RELEVANCE FOR PERSONALIZED THERAPY IN SEVERE HAEMOPHILIA A (PHYSEMO)

Official Title

PHYSICAL ACTIVITY AND FVIII CLEARANCE: RELEVANCE FOR PERSONALIZED THERAPY IN SEVERE HAEMOPHILIA A

Brief Summary

      In persons with severe haemophilia A (HA) infused factor VIII (FVIII) half-life and other
      pharmacokinetic parameters can vary according to determinants such as blood group, von
      Willebrand factor (VWF) level or age. However, FVIII pharmacokinetics (PK) has not been
      thoroughly studied in patients with severe HA as a function of daily physical activity.

      Patients with severe HA (FVIII <1%) are predisposed to prolonged bleeding following even
      minimal musculoskeletal injuries. Potential consequences of repeated musculoskeletal bleeding
      are pain, arthropathy and physical disability. The key standard of care for HA patients is
      prophylactic infusions of FVIII concentrates (25-50 IU kg-1 infused 2-3 x/week), depending on
      individual response.

      The level of infused FVIII decreases as a function of time according to both specific PK
      features of each product and biochemical/genetic characteristics of the patients or different
      clinical conditions.

      Some critical points remain still unraveled, for instance, whether or not FVIII AUC is
      significantly affected by physical activity/exercise, in response to increased metabolic rate
      or subclinical/microhaemorrhages in patients with severe HA.

      It is known that vigorous-intensity physical activity/exercise can transiently but
      significantly increase circulating levels of endogenous VWF and consequently FVIII in normal
      subjects and in patients with moderate or mild haemophilia A. The proposed study is a Proof
      of Concept one as it will be aimed at investigating the relation between daily physical
      activity, measured by SenseWear® armband device, as number of daily steps, and PK variability
      of infused rec-FVIII concentrate. This kind of investigation has never been done and it is a
      great interest also for the evaluation of patients' quality of life.
    

Detailed Description

      Background In persons with severe haemophilia A (HA) infused factor VIII (FVIII) half-life
      and other pharmacokinetic parameters can vary according to determinants such as blood group,
      von Willebrand factor (VWF) level or age [1]. However, FVIII pharmacokinetics (PK) has not
      been thoroughly studied in patients with severe HA as a function of daily physical activity,
      reliably measured with multi-dimensional parameters. Research has indeed demonstrated the
      benefits of physical activity and the negative consequences of sedentary behavior for
      physical and mental wellbeing [2]. Thus, physical activity has become increasingly prominent
      as an intervention tool; however, research is often hindered by the challenge of employing a
      valid, reliable measure that also adequately satisfies the research question or design [2,
      3]. Patients with severe HA (FVIII <1%) are predisposed to prolonged bleeding following even
      minimal musculoskeletal injuries. Potential consequences of repeated musculoskeletal bleeding
      are pain, arthropathy and physical disability [4, 5]. The key standard of care for HA
      patients is prophylactic infusions of FVIII concentrates. Commonly used prophylaxis regimens
      with standard FVIII concentrates are 25-50 IU kg-1 infused 2-3 x/week, depending on
      individual response and/or resource availability of therapeutical products [6]. International
      guidelines also recommend to increase FVIII levels following musculoskeletal or other bleeds
      [6]. The level of infused FVIII decreases as a function of time according to both specific PK
      features of each product and biochemical/genetic characteristics of the patients or different
      clinical conditions. FVIII half-life is approximately 8-12 h [6]. FVIII half-life is
      increased in adult vs. pediatric patients [7, 8], in subjects with higher baseline von
      Willebrand factor (VWF) plasma levels [9, 10] and is decreased in patients with blood group O
      [8, 9]. On the other hand, some critical points remain still unraveled. One may wonder, for
      instance, whether or not FVIII AUC is significantly affected by physical activity/exercise,
      in response to increased metabolic rate or subclinical/microhaemorrhages in patients with
      severe HA [11]. It is known that vigorous-intensity physical activity/exercise can
      transiently but significantly increase circulating levels of endogenous VWF and consequently
      FVIII in normal subjects [12, 13]and in patients with moderate or mild haemophilia A [14,
      15]. The proposed study is a Proof of Concept one as it will be aimed at investigating the
      relation between daily physical activity, measured by SenseWear® armband device, as number of
      daily steps, and PK variability of infused rec-FVIII concentrate. This kind of investigation
      has never been done and it is a great interest also for the evaluation of patients' quality
      of life.

      Study design

      This is a prospective, interventional, low risk, cohort study with device. Twenty patients
      (haemophilia A is a rare disease, hence the investigators are going to enroll in the study
      all the available patients), all consecutively enrolled in a period of 12 months, in the two,
      mentioned above, participant centers, will be followed for 12 months from the enrolment.
      Hence, the planned study period is as follows:

        -  initiation Q1 2019

        -  completion Q3 2020 Eligible patients will be asked not to use FVIII during the 72 hours
           before their baseline visit for the assessment of FVIII PK parameters. Two days before
           their visit to the clinic, patients will be asked to complete a questionnaire to give
           information on their general health status and use of medication in the preceding days.
           At baseline, T=0, following the routine clinical practice in the follow up of
           haemophilic patients, blood samples will be collected by venipuncture into plastic tubes
           containing 0.109 M buffered trisodium citrate in a 9:1 ratio. Blood sample will be taken
           and FVIII PK parameters will be determined and the SenseWear™ Armband will be put on
           place. Then, 50 IU/kg of the FVIII product, regularly used by the patient, will be
           infused. After infusion with FVIII, blood samples will be collected at 30 minutes and 1,
           8, 24, 48 and 72 hours. The blood samples will be centrifuged for 15 minutes at 1500 × g
           (3000 rpm) immediately and plasma will be stored at -80°C.Patients will wear the
           SenseWear™ Armbandfor 7 consecutive days for at least 20 h/day.

      A questionnaire on the quality of life (Haem-A-QoL)[17] will be administered to all enrolled
      patients (see Annex 3), following the routine clinical practice.

      Methods Coagulation and haematology assays All hemostasis-related tests will be performed at
      the Hemostasis and Thrombosis Center of FPG. FVIII activity will be determined using the
      one-stage method. Since inhibitory antibodies against factor VIII may influence FVIII
      half-life, the presence of these antibodies will be assessed in pre-infusion samples using
      the Nijmegen variant of the Bethesda assay [16]. Inhibitor concentrations of >0.6 Bethesda
      Units (BU)/mL will be considered positive. Pre-infusion von Willebrand factor (VWF) antigen
      and activity levels will be determined using an immunometric assay (VWF:Ag and VWF:act) on an
      automatic chemiluminescence instrument (AcuStar, Instrumentation Laboratory, Werfen Group,
      Milano, Italy).

      Method to measure physical activity of patients Physical activity will be measured using the
      SenseWear™ Armband (see the enclosed file for the description of the device's
      characteristics, Annex 2) and the balanced daily energy expenditure, number of steps,
      physical activity intensity (METs) will be monitored for each subject in the period of
      observation. The device is worn over the right triceps brachii muscle and incorporates five
      sensors: two-axis accelerometer (for movement patterns and step-count), galvanic skin
      response, skin temperature, near body temperature sensor and heat flux [1]. According to the
      study protocol, patients will wear the SenseWear™ Armband on 7 consecutive days for at least
      20 h/day. Collected data will be exported via the Professional InnerView Software 7.0 (Body
      Media Inc., Pittsburgh, PA). This software calculates the balanced daily energy expenditure
      (EE) from the sensor parameters together with anthropometric data (gender, age, height,
      weight, BMI, handedness, smoking status). Physical activity intensity is classified by
      Metabolic Equivalents of Task (MET) as defined by Jette et al. [2], which are commonly used
      to classify activities based on their EE.

      Physical Examinations At screening and subsequent study visits a physical examination will be
      performed on the following body systems being described as normal or abnormal: general
      appearance, headand neck, eyes and ears, nose and throat, chest, lungs, heart, abdomen,
      extremities and joints, lymph nodes, skin, and neurological. At screening, if an abnormal
      condition is detected, the condition will be described on the medical history CRF. At study
      visit, if a new abnormal or worsened abnormal pre-existing condition is detected, the
      condition will be described on the CRF.

      Vital Signs Vital signs will include height (cm) and weight (kg). Height and weight will be
      collected,if available, at screening visit and study completion/termination.

      Subject Identification Code The following series of numbers will comprise the subject
      identification code (SIC): protocol acronym (PHYSEMO), and 2-digit subject number (e.g.,
      01….02) reflecting the order of enrollment (i.e., signing the informed consent form). For
      example, the third subject who signed an informed consent form will be identified as
      PHYSEMO-03. All study documents (e.g., CRFs, clinical documentation, etc.) will be identified
      with the SIC.

      Subject completation/discontinuation Reasons for completion/discontinuation will be reported
      on the Completion/ Discontinuation CRF page, including: completed, screen failure, adverse
      event (e.g., death), discontinuation by subject (e.g., lost to follow-up[defined as 3
      documented unsuccessful attempts to contact the subject], dropout),physician decision (e.g.,
      pregnancy, progressive disease, protocol violation(s)). Regardless of the reason, all data
      available for the subject up to the time of completion/ discontinuation should be recorded on
      the appropriate CRF pages. The reason for discontinuation will be recorded on the CRF, and
      data collected up to the time of discontinuation will be used in the analysis and included in
      the clinical study report.

      Procedures for Monitoring Subject Compliance There is no procedure for monitoring subject
      compliance. All treatment regimens and monitoring schedules will be determined by the
      treating physician. The protocol does not require for any additional testing or monitoring
      than what is judged necessary by the treating physician.

      Statistics and data analysis Major baseline demographic, anthropometric and clinical
      variables will be summarized for the enrolled populations. All continuous variables will be
      summarized with means, standard deviations, medians, interquartile ranges, minimums, and
      maximums. Categorical variables will be summarized with frequencies and percentages. Age,
      body mass index, annual bleeding rate (ABR) and Hemophilia Joint Heath Score (HJHS) score
      will be registered at the enrollment visit according to routine good clinical practice for
      heamophilia patients and described statistically. In order to investigate whether the daily
      physical activity level affects the PK parameter: AUC, the correctness of the experience of
      clinicians, which suggests a higher level of physical activity in the 12-35 age group, will
      be demonstrated first. Later the investigators will demonstrate that the mean AUC of the
      12-35 group is significantly smaller than the mean AUC of the 36-60 group, using the
      appropriate test according to the variables' nature. This strategy will allow to analyze the
      influence of physical activity inside each group on PK parameters of patients with more
      homogeneous characteristics.

      Linear regression analysis (bivariate, Spearman method) will be used to assess the relation
      between FVIII PK parameters and several independent variables, such as age, known blood
      group, VWF antigen/activity, physical activity parameters measured using the SenseWear™
      Armband and HJHS score. Furthermore, since the HJHS scores are dependent on age [18, 19], the
      findings will be adjusted for age at HJHS score. The independent variables that will be
      significantly associated with PK parameters (especially half-life and clearance) with p<0.05
      will be analyzed in a multivariable analysis. The validated program MyPK Fit (Shire) will be
      used to calculate FVIII PK parameters. The last five years of follow-up will be used to
      estimate annual clotting factor use (IU/kg/yr), number of joint bleeds per year and weekly
      dose on prophylaxis (IU/kg/wk).

      All the tests will be performed considering a level of confidence alpha=0.05. Analyses will
      be performed using SPSS software (version 21, Chicago, IL, USA) and GraphPad Prism software
      (GraphPad Software, Inc, La Jolla, CA, USA).

      Sample Size Calculation Dealing with a rare disease and considering the amount of eligible
      patients available from both the centres, the expected sample size is roughly N=20 patients.
      A significant difference in daily physical activity level of at least 2000 steps was defined
      as the primary end-point and the level of physical activity corresponding to 6000 ± 2000 and
      12000 ± 1000 steps was assumed for 36-60 and 12-35 years groups, respectively. A sample size
      of 10 subjects in each group was estimated for 80% power and alfa 0.05.

      Handling of Missing, Unused, and Spurious Data Analyses will exclude missing data. Unused and
      spurious data will be listed in the Clinical Study Report to include the reason(s).

      Ethics Committee and Regulatory Authorities Before enrollment of patients into this study,
      the protocol, informed consent form (see Annex 3), any promotional material/advertisements,
      and any other written information to be provided will be reviewed and approved/given
      favorable opinion by the EC and applicable regulatory authorities.

      If the protocol or any other information given to the subject is amended, the revised
      documents will be reviewed and approved/given favorable opinion by the EC and applicable
      regulatory authorities, where applicable. The protocol amendment will only be implemented
      upon the sponsor's receipt of approval and, if required, upon the sponsor's notification of
      applicable regulatory authority(ies) approval.

      Informed Consent Investigators will choose patients for enrollment based on the study
      eligibility criteria.

      The investigator will exercise no selectivity so that no bias is introduced from this source.

      All patients must sign an informed consent form before entering into the study according to
      applicable regulatory requirements. Before use, the informed consent form will be reviewed by
      the EC. The informed consent form will include a comprehensive explanation of the proposed
      treatment without any exculpatory statements. Patients will be allowed sufficient time to
      consider participation in the study. By signing the informed consent form, patients agree to
      take part in the study.

      Confidentiality Policy The investigator will comply with the confidentiality policy as
      described in the Non-Interventional Trial Agreement.

      Study Documents and Case Report Forms The investigator will maintain complete and accurate
      study documentation in a separate file. Documentation may include medical records, records
      detailing the progress of the study for each subject, signed informed consent forms,
      correspondence with the EC, enrollment and screening information, CRFs and laboratory
      reports. The investigator will comply with the procedures for data recording and reporting.
      Any corrections to study documentation must be performed as follows: 1) the first entry will
      be crossed out entirely, remaining legible; and 2) each correction must be dated and
      initialed by the person correcting the entry; the use of correction fluid and erasing are
      prohibited.

      Case Report Forms The investigator is responsible for the procurement of data and for the
      quality of data recorded on the CRFs. CRFs will be provided in paper form.

      Only authorized study site personnel will record or change data on the CRFs. All data should
      preferably be entered on the CRFs during the study visit. Changes to a CRF will require
      documentation of the reason for each change.

      The handling of data by the sponsor, including data quality assurance, will comply with
      regulatory guidelines and the standard operating procedures of the sponsor. Data management
      and control processes specific to the study will be described in the data management plan.

      Document and Data Retention The investigator will retain study documentation and data in
      accordance with applicable regulatory requirements and the document and data retention
      policy, as described in the Non-Interventional Study Agreement.
    


Study Type

Interventional


Primary Outcome

Study of the association between physical activity, measured by mean number of daily steps, with the Area Under the Curve (AUC) PK parameter in patients with severe HA under prophylaxis.

Secondary Outcome

 Study of the association between physical activity, measured by the mean number of daily steps, with the clearance (U/ml/hr) of FVIII concentrate PK parameters in patients with severe HA.

Condition

Hemophilia A

Intervention

SenseWear® armband device

Study Arms / Comparison Groups

 Patients with severe HA under FVIII concentrates prophylaxis
Description:  

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Device

Estimated Enrollment

20

Start Date

January 9, 2020

Completion Date

December 30, 2020

Primary Completion Date

December 30, 2020

Eligibility Criteria

        Inclusion Criteria:

          -  Patients (12-60 yr. old) with severe HA under FVIII concentrates prophylaxis will be
             selected at the Haemostasis and Thrombosis Center of the Fondazione Policlinico
             Universitario "A. Gemelli", IRCCS, Rome, Italy (FPG) and at the satellite site at the
             Department of Cellular Biotechnology and Haemathology, Policlinico Umberto I, Sapienza
             University of Rome, Italy (UNSA_SS).

        Exclusion Criteria:

          -  All patients with malignant tumors, or treated with anticoagulant / antiplatelet
             agents, and suffering from other congenital coagulation disorders (von disease
             Willebrand disease, other congenital deficiency of coagulation factors) or severe
             thrombocytopenia (<30,000 Plt /μL).

        Patients who would have undergone a severe bleed or surgery during the past 3 months before
        enrolment.
      

Gender

Male

Ages

12 Years - 60 Years

Accepts Healthy Volunteers

No

Contacts

, , 

Location Countries

Italy

Location Countries

Italy

Administrative Informations


NCT ID

NCT04303936

Organization ID

2364


Responsible Party

Principal Investigator

Study Sponsor

Catholic University of the Sacred Heart


Study Sponsor

, , 


Verification Date

March 2020