A Long-Term Follow-Up Study of Haemophilia B Patients Who Have Undergone Gene Therapy

An Open-Label, Multicentre, Long-Term Follow-Up Study to Investigate the Safety and Durability of Response Following Dosing of a Novel Adeno-Associated Viral Vector (FLT180a) in Patients With Haemophilia B

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 Overview

• Status: Terminated
• Conditions: Hemophilia B
• Intervention / Treatment: Biological: FLT180a

• Study Type: Interventional
• Enrollment (Actual): 10
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United Kingdom
  • London, United Kingdom
    • Royal Free London NHS Foundation Tust
  • Newcastle, United Kingdom, NE14LP
    • Newcastle Hemophilia Comprehensive Care Centre
  • Oxford, United Kingdom
    • Oxford University Hospitals NHS Foundation Trust
  • Southampton, United Kingdom, SO166YD
    • Southampton Haemophilia Comprehensive Care Centre
  • Kent
    • Canterbury, Kent, United Kingdom, CT13NG
      • The Haemophilia and Thrombosis Centre
  • South Yorkshire
    • Sheffield, South Yorkshire, United Kingdom, S102JF
      • Sheffield Teaching Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients who have previously received FLT180a within a clinical study.
• Able to give full informed consent and able to comply with all requirements of the study including long-term follow-up for the time frame the study requires.
• Willing to practice barrier contraception until at least three consecutive semen samples after vector administration are negative for vector sequences.

Exclusion Criteria:

N/A

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: FLT180a; Participants who have received gene therapy vector (FLT180a)	Biological: FLT180a; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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).	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)	From entry to 5 years post dosing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	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.	From entry to complete clearance of vgs in all sample pools.

Collaborators and Investigators

• Sponsor: Freeline Therapeutics

Publications and helpful links

General Publications

• Chowdary P, Shapiro S, Makris M, Evans G, Boyce S, Talks K, Dolan G, Reiss U, Phillips M, Riddell A, Peralta MR, Quaye M, Patch DW, Tuddenham E, Dane A, Watissee M, Long A, Nathwani A. Phase 1-2 Trial of AAVS3 Gene Therapy in Patients with Hemophilia B. N Engl J Med. 2022 Jul 21;387(3):237-247. doi: 10.1056/NEJMoa2119913.

Study record dates

Study Major Dates

• Study Start (Actual): July 10, 2018
• Primary Completion (Actual): May 24, 2023
• Study Completion (Actual): May 24, 2023

Study Registration Dates

• First Submitted: July 27, 2018
• First Submitted That Met QC Criteria: August 20, 2018
• First Posted (Actual): August 22, 2018

Study Record Updates

• Last Update Posted (Actual): July 20, 2023
• Last Update Submitted That Met QC Criteria: July 18, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Blood Coagulation Disorders; Hemophilia A; Hemophilia B
• Other Study ID Numbers: FLT180a-04

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No