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A Factor IX Gene Therapy Study (FIX-GT) (FIX-GT)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03369444
Recruitment Status : Recruiting
First Posted : December 12, 2017
Last Update Posted : March 13, 2020
Sponsor:
Information provided by (Responsible Party):
University College, London

Brief Summary:

Severe haemophilia B 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 haemophilia B, levels of clotting factor IX (FIX) (nine) are very low and affected individuals can suffer life threatening bleeding episodes. HB mainly affects boys and men (normally one in every 30,000 males). Current treatment for HB involves intravenous infusions of factor IX as regular treatment (Prophylaxis) or 'on demand'. 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 can be invasive for patients and also expensive. This research study aims to test the safety and effectiveness of a gene therapy which produces Factor IX protein in the body. The gene will be given using an inactivated virus called "the vector" ( FLT180a), in a single infusion. The vector has been developed from a virus known as an adeno- associated virus, that has been changed so that it is unable to cause a viral infection in humans. This "inactivated" virus is further altered to carry the Factor IX gene and to make its way within liver cells where Factor IX protein is normally made.

Up to three different doses of FLT180a will be tested, in up to 18 patients with severe haemophilia B. Patients will be recruited from haemophilia centres in the EU and US. Patients will be in the trial for approximately 40 weeks and will undergo procedures including physical examinations, bloods tests, ECGs and liver ultrasounds.


Condition or disease Intervention/treatment Phase
Hemophilia B Biological: FLT180a Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II, Open Label, Multicentre, Ascending Single Dose, Safety Study of a Novel Adeno- Associated Viral Vector (FLT180a) in Patients With Haemophilia B
Actual Study Start Date : December 5, 2017
Estimated Primary Completion Date : January 1, 2021
Estimated Study Completion Date : June 1, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: FLT180a Treatment
Participants receiving gene therapy vector
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.




Primary Outcome Measures :
  1. Frequency and severity of treatment-emergent Adverse Events (Safety) [ Time Frame: From screening until week 26 post infusion ]
    Adverse events will be coded using CTCAE version 4.03. Frequency of treatment-emergent AEs will be calculated for each body system and preferred term, and by dose cohort, for number of events and number of patients reporting the event. The severity of the AEs and the relationship to study medication will be summarised for each body system and preferred term by cohort.


Secondary Outcome Measures :
  1. Endogenous FIX production [ Time Frame: From screening until week 26 post infusion ]
    The proportion of patients achieving clinical FIX response at Week 26, at the terminal dose level. A clinical FIX response is defined as achieving a FIX activity of 5% to 150%.

  2. hFIX activity change from baseline [ Time Frame: From screening until week 26 post infusion ]
    The proportion of patients also achieving normalised FIX response at Week 26, at the terminal dose level. A normalised FIX response is defined as achieving FIX activity in the normal range (50-150%)

  3. FIX concentrate usage [ Time Frame: From screening until week 26 post infusion ]
    Change from baseline in FIX concentrate consumption.

  4. Bleeding Frequency [ Time Frame: From screening until week 26 post infusion ]
    Change from baseline in annualised bleeding rate

  5. Immune response - development of inhibitors [ Time Frame: From screening until week 26 post infusion ]
    Immune response to the hFIX transgene product (i.e., development of inhibitors) will be assessed by measurement of the level of inhibitors.

  6. Immune response to AAV capsid [ Time Frame: From screening until week 26 post infusion ]
    Immune response to the AAV capsid will be assessed by measurement of the neutralising antibody titre.

  7. T-cell response to AAV capsid [ Time Frame: From screening until week 26 post infusion ]
    T-cell responses to AAV capsid will be assessed in peripheral blood mononuclear cells.

  8. Viral Shedding [ Time Frame: From screening until week 26 post infusion ]
    Serum and bodily secretions will be collected to assess clearance of vector genomes


Other Outcome Measures:
  1. Disability status [ Time Frame: From screening until week 26 post infusion ]
    Change from baseline in World Health Organization Disability Assessment Schedule 2.0 score.

  2. Physical activity [ Time Frame: From screening until week 26 post infusion ]
    Change from baseline in Haemophilia Activities List (HAL) 2005.

  3. Health-related quality of life [ Time Frame: From screening until week 26 post infusion ]
    Change from baseline in the EQ-5D-5L and Haem-A-QoL score.

  4. Health-related quality of life [ Time Frame: From screening until week 26 post infusion ]
    Change from baseline in the PROBE score.

  5. Assessment of joint health/function [ Time Frame: From screening until week 26 post infusion ]
    Change from baseline in the Haemophilia Joint Health Score (HJHS).

  6. Health resource utilisation - haemophilia related medical appointments [ Time Frame: From screening until week 26 post infusion ]
    Assessment of health resource utilisation based on number of haemophilia related medical appointments and medical activities

  7. Health resource utilisation - number of emergency room visits [ Time Frame: From screening until week 26 post infusion ]
    Assessment of health resource utilisation based on number of emergency room visits

  8. Health resource utilisation - number of hospitalisations [ Time Frame: From screening until week 26 post infusion ]
    Assessment of health resource utilisation based on number of hospitalisations related to haemophilia

  9. Health resource utilisation - length of hospital stays [ Time Frame: From screening until week 26 post infusion ]
    Assessment of health resource utilisation based on length of haemophilia related hospital stays

  10. Health resource utilisation - work and education days lost [ Time Frame: From screening until week 26 post infusion ]
    Assessment of health resource utilisation based on number of days lost from education or work due to bleeding episodes

  11. Health resource utilisation - physiotherapy and professional sessions [ Time Frame: From screening until week 26 post infusion ]
    Assessment of health resource utilisation based on number of physiotherapy sessions, specialist consultations and appointments with professional caregivers.

  12. Health resource utilisation - visits to site [ Time Frame: From screening until week 26 post infusion ]
    Assessment of health resource utilisation based on number of visits to site



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Adults males, ≥ 18 years of age;
  2. Confirmed diagnosis of HB defined as one of the following:

    Documented severe FIX deficiency with plasma FIX activity of <1% of normal or moderately severe FIX deficiency with plasma FIX activity level between ≥1% and ≤2% and a severe bleeding phenotype defined by one of the following:

    1. On prophylaxis for a history of bleeding, or
    2. On-demand therapy with a current or past history of 4 or more bleeding episodes/year, or
    3. Evidence of chronic haemophilic arthropathy (pain, joint destruction, and loss of range of motion).
  3. Able to give full informed consent and able to comply with all requirements of the trial including 15-year long-term follow-up;
  4. Willing to practice barrier contraception until at least two consecutive semen samples after vector administration are negative for vector sequences;
  5. Lack of neutralising anti-AAV antibodies using an in-vivo transduction inhibition assay;
  6. At least 150 exposure days to FIX concentrates.

Exclusion Criteria:

  1. Presence of neutralising antihuman FIX antibodies (inhibitor, determined by the Bethesda inhibitor assay) at the time of enrolment or a previous history of FIX inhibitor.
  2. Patients at high risk of thromboembolic events (high risk patients would include those with a history of arterial or venous thromboembolism (e.g. deep vein thrombosis, pulmonary embolism, non-haemorrhagic stroke, arterial embolus) and those with acquired thrombophilia including conditions such as atrial fibrilation).
  3. Use of investigational therapy for haemophilia within 30 days before enrolment.
  4. Patients with active hepatitis B or C, and HBsAg or hepatitis C virus (HCV) RNA viral load positivity, respectively, or currently on antiviral therapy for hepatitis B or C. Negative viral assays in 2 samples, collected at least 6 months apart, will be required to be considered negative. Both natural clearers and those who have cleared HCV on antiviral therapy are eligible.
  5. Serological evidence of HIV-1.
  6. Evidence of liver dysfunction (persistently elevated alanine aminotransferase, aspartate aminotransferase, bilirubin >1.5 x upper limit of normal).
  7. Plateletcount<50x109/L.
  8. Uncontrolled glaucoma, diabetes mellitus, or hypertension.
  9. Malignancy requiring treatment.
  10. Patients with uncontrolled cardiac failure, unstable angina or myocardial infarction in the past 6 months.
  11. Poor performance status (World Health Organization score >1).
  12. Prior treatment with any gene transfer medicinal product.
  13. Known or suspected intolerance, hypersensitivity or contrainidication to the investigational product and non-investigational medicinal products or their excipients;
  14. Planned major elective surgery prior to the end of trial.
  15. Current or relavant history of a physical or psychiatric illness or any medicial condition that in the opinion of the investigator could affect the patients safety or interfere with the study assessments.
  16. CMV IgG postive patients who are CMV PCR positive at screening.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03369444


Contacts
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Contact: Pratima Chowdary 02078302068 p.chowdary@nhs.net
Contact: Mark Phillips 0207 794 0500 ext 38784 mark.phillips12@nhs.net

Locations
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United States, Tennessee
St Jude Children's Research Hospital Recruiting
Memphis, Tennessee, United States, 38119
Contact: Ulrike Reiss         
Italy
University of Milan Recruiting
Milan, Italy
Contact: Flora Peyvandi         
United Kingdom
Basingstoke Haemostasis and Thrombosis Centre Recruiting
Basingstoke, United Kingdom
Contact: Sarah Mangles         
East Kent Hospitals University Recruiting
Canterbury, United Kingdom
Contact: Gillian Evans         
Guy's and St Thomas's NHS Foundation Trust Recruiting
London, United Kingdom
Contact: Gerald Dolan         
Royal Free Hospital Recruiting
London, United Kingdom
Contact: Pratima Chowdary         
Newcastle Hospitals NHS Trust Recruiting
Newcastle Upon Tyne, United Kingdom
Contact: Kate Talks         
Oxford University Hospital Recruiting
Oxford, United Kingdom
Contact: Susie Shapiro         
University of Sheffield Recruiting
Sheffield, United Kingdom
Contact: Mike Makris         
University Hospital Southampton Recruiting
Southampton, United Kingdom
Contact: Sara Boyce         
Sponsors and Collaborators
University College, London
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Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT03369444    
Other Study ID Numbers: UCL/15/0552
First Posted: December 12, 2017    Key Record Dates
Last Update Posted: March 13, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Hemophilia A
Hemophilia B
Blood Coagulation Disorders, Inherited
Blood Coagulation Disorders
Hematologic Diseases
Coagulation Protein Disorders
Hemorrhagic Disorders
Genetic Diseases, Inborn
Genetic Diseases, X-Linked