A Follow-Up Study of Haemophilia B Patients after Gene Therapy
Research type
Research Study
Full title
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
IRAS ID
241903
Contact name
Pratima Chowdary
Contact email
Sponsor organisation
Freeline Therapeutics Ltd
Eudract number
2017-005080-40
Duration of Study in the UK
17 years, 6 months, 1 days
Research summary
Research Summary:
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 research 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 in the trial for approximately 14 years 6 months and will undergo procedures including physical examinations, bloods tests and liver ultrasounds. Participants will also need to complete a diary to document occurrence of bleeding episodes and the consumption of FIX as well as completing patient reports outcomes to assess Quality of Life, disability and physical activity.
Lay summary of study results: "Freeline Therapeutics Ltd (“Freeline”) sponsored this trial and would like to acknowledge the contribution of the trial participants to this research.
What was the trial about?
This is a follow-up trial of 10 participants with haemophilia B in the United Kingdom who previously were in the 15/0552 trial. In the 15/0552 trial, these 10 participants were given the gene therapy known as FLT180a as a one-time, slow injection through a needle into a vein, also known as an intravenous (IV) infusion.The health of all participants who took part in the trial was checked regularly by Freeline for about 5 years after the previous trial (15/0552) ended.
The trial was cancelled early by Freeline for commercial reasons. Freeline reviewed the data collected when this trial ended and created a report of the results. This is a summary of the main results.
Why was the research needed?
Haemophilia B is a bleeding disorder that happens mostly in males. Most cases of haemophilia B are inherited, which means it is passed down to someone through their parents’ genes. Normally, the body uses a protein called “factor IX” or “factor 9” to make blood clots when you cut yourself or have an operation. In people with haemophilia B, the body does not make enough factor IX to make blood clot, as the gene that provides instructions for making factor IX in the body is missing or faulty. Without enough factor IX, the blood cannot clot. This can lead to bleeding that does not stop, including bleeding inside the body.Current treatments for haemophilia B work by replacing the missing factor IX. Normally, factor IX replacements need to be given as IV infusions. Getting IV infusions can sometimes cause medical problems such as infections. The infusions can also be very time-consuming and have a major impact on the person’s life.
Researchers are looking for better ways to treat people with moderate or severe haemophilia B. Before a new treatment can be approved for patients to receive as standard of care, researchers conduct clinical trials to find out how it works and how safe it is.
This trial looked at the long-term safety and effect of the trial treatment, FLT180a, which is a type of treatment called “gene therapy”. Instead of replacing the body’s missing factor IX, gene therapy introduces a working copy of the gene into the body that provides the correct instructions. The body then uses the new instructions to produce its own factor IX. This could mean that people with haemophilia B might not need to have regular factor IX replacement infusions.
What kind of trial was this?
This trial was an “open-label” trial. This means the researchers and the participant knew what treatment each participant received.This was also a long-term follow-up trial, which means that participants who were monitored to examine the safety and effect of FLT180a for a long period of time after they received trial treatment. This trial began immediately after the previous trial was completed and lasted approximately 5 years.
For this trial, participants completed follow-up visits. During these visits, information on the participants’ overall health, medical problems, and response to treatment was collected.
Who did the trial enrol?
The participants of this trial had either severe or moderately severe haemophilia B. To take part in the trial, the participants must have taken part in the previous trial, 15/0552.What questions did the trial want to answer?
The main questions the researchers wanted to answer in this trial were:
• What medical problems did participants have during the trial?
• What did factor IX activity levels look like after participants were given FLT180a from the previous trial?What type of treatments did the participants receive?
Participants did not receive treatment in this trial but did receive treatment in the previous trial (15/0552), where participants received FLT180a through an IV infusion. Ten participants received 4 different doses of FLT180a: 6 × 1011 vg/kg, 2 × 1012 vg/kg, and 1 × 1012 vg/kg (2 participants each); and 1.3 × 1012 vg/kg (4 participants).What happened during the trial?
Before the trial, the participants were given their FLT180a in the previous trial. Participants who completed the previous trial were invited by the sponsor to continue (“rollover”) in this long-term follow-up trial.Six months after receiving treatment and approximately around the time of rollover into this trial, the doctors checked participants’ overall health to make sure they could remain in the trial. The doctors checked the participants’ blood pressure, joint health, and took blood samples. They also asked about the participants’ medical history. Participants also had a liver scan and their hearts monitored. The participants were also required to answer questionnaires about their symptoms and quality of life and to keep a diary during the trial.
During the trial, the participants completed follow-up visits at the trial sites. Participants’ data were collected every month (for up to 2 years), every 6 months (during the third year of the trial), or every year (during the fourth and fifth year). Participants received check-ups to assess medical problems, have liver scans, assess if the treatment can be excreted from the body, and to assess how the immune system reacted to treatment.
The last visit took place at the trial site, approximately 5 years after the participants were administered FLT180a in the previous trial. Freeline decided to cancel the trial for commercial reasons.
What were the results of the trial?
This is a summary of the main results from this trial overall. The results each participant had might be different from the overall summary results.A full list of the questions the researchers wanted to answer can be found on the websites listed at the end of this summary. Once a full report of the trial results is available, it may also be found on these websites.
What medical problems did any participants have during the trial?
This section is a summary of the “adverse events” that happened during this long-term follow-up trial. An adverse event is any new sign or symptom that participants have, which may or may not be caused by the treatments in the trial. In this follow-up trial, all participants had at least 1 adverse event within the first year they were given FLT180a. Most of these adverse events were alanine aminotransferase (ALT) increased, diarrhoea, arthralgia (joint stiffness), and headaches. The number of adverse events decreased after the first year following FLT180a treatment.Most trial participants’ immune systems reacted to FLT180a, which in some cases caused adverse events. these events were treated with a medicine (an immunosuppressant) that decreased the body’s immune response.
How many participants had serious adverse events?
An adverse event is called “serious” when it is life-threatening, causes lasting problems, is medically significant, requires hospital care, or results in death.2 out of 10 participants had serious adverse events during this trial. This was 20% of participants. One participant had a serious adverse event of arteriovenous fistula thrombosis (a blood clot that forms inside a patient’s arteriovenous fistula – an irregular pathway between an artery and vein) within the first year following FLT180a, while another participant had an event of appendicitis (swelling of the appendix) that occurred between 1 to 2 years after they were given FLT180a. The researchers determined that these 2 serious adverse events were not related to FLT180a. Between the 2 and 4 years of follow-up (before the trial was cancelled after 5 years), there were no serious adverse events reported in the trial.
None of the participants died during this trial.
What did factor IX activity levels look like after participants were given FLT180a from the previous trial?
In the previous trial, the factor IX activity levels went from a low to normal range. In this trial, factor IX activity levels remained at a normal range following treatment for participants overall. Factor IX activity levels remained stable over time.How has this trial helped patients and researchers?
This trial helped researchers to learn more about the long-term safety of FLT180a and how well it works when given to people with haemophilia B.The results of this trial showed that FLT180a was well-tolerated in all participants and had a good safety profile. Researchers look at the results of many trials to decide which treatments work best and are safest for patients. This summary shows only the main results from one trial. Other trials may provide new information or different results. Always talk to a doctor before making any treatment changes."
REC name
London - West London & GTAC Research Ethics Committee
REC reference
18/LO/0508
Date of REC Opinion
2 May 2018
REC opinion
Favourable Opinion