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

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.