Severe haemophilia B (HB) is a bleeding disorder where a protein made by the body to help make blood clot is either partly or completely missing. This protein is called a clotting factor; with severe HB, levels of clotting Factor IX (nine; FIX) are very low and affected individuals can suffer life threatening bleeding episodes. HB mainly affects boys and men (approximately one in every 30,000 males). Current treatment for HB involves intravenous infusions of FIX as regular treatment (prophylaxis) or 'on demand' treatment. On demand treatment is highly effective at stopping bleeding but cannot fully reverse long-term damage that follows after a bleed. Regular treatment can prevent bleeding; however it is invasive for patients and also expensive. This clinical study aims to investigate the long-term safety and durability of FIX activity in participants who have been dosed with a new gene therapy product (FLT180a) in earlier clinical studies. Following administration, FLT180a results in production of FIX in the participants' liver cells which is then released into the blood stream. The aim is to have the participants' own body produce levels of FIX that allow for clotting to occur as normal as would be seen in a non-HB individual. This would remove the need for prophylaxis or on demand treatment following just a single administration of FLT180a. Up to 50 participants who have already been administered with FLT180a in the EU and US will take part in this study. Participants will be followed up in this trial until they have reached 15 years after being dosed. Participants will undergo procedures including physical examinations, join assessments, blood tests and liver ultrasounds. Participants will also need to complete a diary to document occurrence of bleeding episodes and record the amount of Factor IX concentrate they receive. Patient reports outcomes including measures of Quality of Life, disability and physical activity will also be collected.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
10
FLT180a is a replication-incompetent adeno-associated viral vector. The vector is composed of a DNA vector genome encapsidated in an adeno-associated virus derived protein capsid. The expression cassette contains DNA encoding Factor IX.
The Haemophilia and Thrombosis Centre
Canterbury, Kent, United Kingdom
Sheffield Teaching Hospital
Sheffield, South Yorkshire, United Kingdom
Royal Free London NHS Foundation Tust
London, United Kingdom
Newcastle Hemophilia Comprehensive Care Centre
Newcastle, United Kingdom
Oxford University Hospitals NHS Foundation Trust
Oxford, United Kingdom
Southampton Haemophilia Comprehensive Care Centre
Southampton, United Kingdom
Primary Safety Measurement
Frequency of treatment-emergent adverse events/reactions (AE/ARs) reported according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 or later (Primary Safety).
Time frame: From entry to 5 years post dosing
Durability of Response
Durability of response will be estimated by the rate of decline of the FIX activity observed from study entry (Primary Endpoint)
Time frame: From entry to 5 years post dosing
Secondary Safety Measurement
Frequency of reporting of abnormal or change from baseline findings from safety assessments including laboratory assessments, vital signs, physical exam and liver ultrasound according to common terminology criteria for Adverse Events (CTCAE) version 5.0 or later.
Time frame: From entry to 5 years post dosing
FIX Activity Levels at or below 150%
Samples will be taken at each visit to measure FIX activity levels and the proportion of patients achieving FIX activity at or above 5%, 15%, 30%, 40%, 50%, 70% but no more than 150% of normal at each scheduled visit.
Time frame: From entry to 5 years post dosing
FIX Activity Levels including 150% or above
Samples will be taken at each visit to measure FIX activity levels and the proportion of patients achieving FIX activity at or above 5%, 15%, 30%, 40%, 50%, 70% and 150% of normal at each required visit.
Time frame: From entry to 5 years post dosing
FIX Activity Levels - Change from baseline
Change from baseline (prior to FLT180a dosing) in FIX activity at each scheduled visit.
Time frame: From entry to 5 years post dosing
Haemostatic Effectiveness - Bleeding Rates
Change from baseline (prior to FLT180a dosing) in annualised bleeding rate by measurement of number of breakthrough bleeding episodes.
Time frame: From entry to 5 years post dosing
Haemostatic Effectiveness - FIX Concentrate Consumption
Change from baseline (prior to FLT180a dosing) in FIX concentrate consumption by measurement of factor concentrate consumed by the patient.
Time frame: From entry to 5 years post dosing
FLT180a effectiveness related to surgical/dental procedures by assessment of consumption of exogenous clotting factors at Time of surgery, Time of drain removal (if applicable)
Consumption of exogenous clotting factors, related to an individual surgery, will be collected at the three time-points (time of surgery, time of drain removal (if applicable) and time of discharge or 6-days post surgery) for each surgery occurring from patient entry into trial until 5 years post-dosing.
Time frame: From entry to 5 years post dosing
FLT180a effectiveness related to surgical/dental procedures by assessment of measurement of absolute blood loss at Time of surgery, Time of drain removal (if applicable)
Measurement of absolute blood loss, related to an individual surgery, will be collected at the three time-points (Time of surgery, Time of drain removal (if applicable) and The earlier of discharge of 6-days post surgery) for each surgery occurring from patient entry into trial until 5 years post-dosing.
Time frame: From entry to 5 years post dosing
FLT180a effectiveness related to surgical/dental procedures by assessment of blood transfusion requirement, volume and number of transfusions at Time of surgery, Time of drain removal (if applicable)
Transfusion requirement (volume and number of transfusions), related to an individual surgery, will be collected at the three time-points (Time of surgery, Time of drain removal (if applicable) and The earlier of discharge of 6-days post surgery) for each surgery occurring from patient entry into trial until 5 years post-dosing.
Time frame: From entry to 5 years post dosing
FLT180a effectiveness related to surgical/dental procedures by assessment of efficacy of haemostasis as judged by surgeon on a 4-point scale at Time of surgery, Time of drain removal (if applicable)
Assessment of efficacy of haemostasis as judged by surgeon, related to an individual surgery, will be collected at the three time-points (Time of surgery, Time of drain removal (if applicable) and The earlier of discharge of 6-days post surgery) for each surgery occurring from patient entry into trial until 5 years post-dosing.
Time frame: From entry to 5 years post dosing
Immune response to the hFIX transgene product (i.e., development of inhibitors) will be assessed by measurement of the level of inhibitors.
Samples will be taken to capture development of inhibitors overtime.
Time frame: From entry to 5 years post dosing
Clearance of vector genomes (vgs) in plasma, urine, saliva, stool and semen.
Samples from each pool will be taken at each visit until there have been 3 consecutive samples that are negative for vgs.
Time frame: From entry to complete clearance of vgs in all sample pools.
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