Ignite Creation Date:
2024-05-06 @ 2:24 PM
Last Modification Date:
2024-10-26 @ 1:30 PM
Study NCT ID:
NCT04303936
Status:
UNKNOWN
Last Update Posted:
2020-03-11
First Post:
2020-01-16
Brief Title:
PHYSICAL ACTIVITY AND FVIII CLEARANCE RELEVANCE FOR PERSONALIZED THERAPY IN SEVERE HAEMOPHILIA A PHYSEMO
Sponsor:
Catholic University of the Sacred Heart
Organization:
Catholic University of the Sacred Heart
Study Overview
Official Title:
PHYSICAL ACTIVITY AND FVIII CLEARANCE RELEVANCE FOR PERSONALIZED THERAPY IN SEVERE HAEMOPHILIA A
Status:
UNKNOWN
Status Verified Date:
2020-03
Last Known Status:
RECRUITING
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PHYSEMO
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 xweek 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 biochemicalgenetic 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 activityexercise in response to increased metabolic rate or subclinicalmicrohaemorrhages in patients with severe HA
It is known that vigorous-intensity physical activityexercise 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
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 xweek 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 biochemicalgenetic 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 activityexercise in response to increased metabolic rate or subclinicalmicrohaemorrhages in patients with severe HA
It is known that vigorous-intensity physical activityexercise 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 xweek depending on individual response andor 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 biochemicalgenetic 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 activityexercise in response to increased metabolic rate or subclinicalmicrohaemorrhages in patients with severe HA 11 It is known that vigorous-intensity physical activityexercise can transiently but significantly increase circulating levels of endogenous VWF and consequently FVIII in normal subjects 12 13and 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 T0 following the routine clinical practice in the follow up of haemophilic patients blood samples will be collected by venipuncture into plastic tubes containing 0109 M buffered trisodium citrate in a 91 ratio Blood sample will be taken and FVIII PK parameters will be determined and the SenseWear Armband will be put on place Then 50 IUkg 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 -80CPatients will wear the SenseWear Armbandfor 7 consecutive days for at least 20 hday
A questionnaire on the quality of life Haem-A-QoL17 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 06 Bethesda Units BUmL will be considered positive Pre-infusion von Willebrand factor VWF antigen and activity levels will be determined using an immunometric assay VWFAg and VWFact 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 devices 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 hday Collected data will be exported via the Professional InnerView Software 70 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 collectedif available at screening visit and study completiontermination
Subject Identification Code The following series of numbers will comprise the subject identification code SIC protocol acronym PHYSEMO and 2-digit subject number eg 0102 reflecting the order of enrollment ie 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 eg CRFs clinical documentation etc will be identified with the SIC
Subject completationdiscontinuation Reasons for completiondiscontinuation will be reported on the Completion Discontinuation CRF page including completed screen failure adverse event eg death discontinuation by subject eg lost to follow-updefined as 3 documented unsuccessful attempts to contact the subject dropoutphysician decision eg pregnancy progressive disease protocol violations 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 antigenactivity 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 p005 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 IUkgyr number of joint bleeds per year and weekly dose on prophylaxis IUkgwk
All the tests will be performed considering a level of confidence alpha005 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 N20 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 005
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 reasons
Ethics Committee and Regulatory Authorities Before enrollment of patients into this study the protocol informed consent form see Annex 3 any promotional materialadvertisements and any other written information to be provided will be reviewed and approvedgiven 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 approvedgiven favorable opinion by the EC and applicable regulatory authorities where applicable The protocol amendment will only be implemented upon the sponsors receipt of approval and if required upon the sponsors notification of applicable regulatory authorityies 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 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 T0 following the routine clinical practice in the follow up of haemophilic patients blood samples will be collected by venipuncture into plastic tubes containing 0109 M buffered trisodium citrate in a 91 ratio Blood sample will be taken and FVIII PK parameters will be determined and the SenseWear Armband will be put on place Then 50 IUkg 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 -80CPatients will wear the SenseWear Armbandfor 7 consecutive days for at least 20 hday
A questionnaire on the quality of life Haem-A-QoL17 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 06 Bethesda Units BUmL will be considered positive Pre-infusion von Willebrand factor VWF antigen and activity levels will be determined using an immunometric assay VWFAg and VWFact 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 devices 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 hday Collected data will be exported via the Professional InnerView Software 70 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 collectedif available at screening visit and study completiontermination
Subject Identification Code The following series of numbers will comprise the subject identification code SIC protocol acronym PHYSEMO and 2-digit subject number eg 0102 reflecting the order of enrollment ie 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 eg CRFs clinical documentation etc will be identified with the SIC
Subject completationdiscontinuation Reasons for completiondiscontinuation will be reported on the Completion Discontinuation CRF page including completed screen failure adverse event eg death discontinuation by subject eg lost to follow-updefined as 3 documented unsuccessful attempts to contact the subject dropoutphysician decision eg pregnancy progressive disease protocol violations 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 antigenactivity 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 p005 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 IUkgyr number of joint bleeds per year and weekly dose on prophylaxis IUkgwk
All the tests will be performed considering a level of confidence alpha005 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 N20 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 005
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 reasons
Ethics Committee and Regulatory Authorities Before enrollment of patients into this study the protocol informed consent form see Annex 3 any promotional materialadvertisements and any other written information to be provided will be reviewed and approvedgiven 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 approvedgiven favorable opinion by the EC and applicable regulatory authorities where applicable The protocol amendment will only be implemented upon the sponsors receipt of approval and if required upon the sponsors notification of applicable regulatory authorityies 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
True
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None