A phase I/II, open-label, uncontrolled, single-dose, dose-ascending, multi-centre trial investigating an adeno-associated viral vector containing a codon-optimized human factor IX gene (AAV5-hFIX) administered to adult patients with severe or moderately severe haemophilia B
- Conditions
- 1000533010064477Christmas disease
- Registration Number
- NL-OMON46967
- Lead Sponsor
- uniQure biopharma B.V.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 8
1. Male
2. Age * 18 years
3. Patients with congenital haemophilia B classified as one of the following:
- Known severe FIX deficiency with plasma FIX activity level <1% and a severe bleeding phenotype defined by one of the following:
o Currently on prophylactic FIX replacement therapy for a history of bleeding
o Currently on on-demand FIX replacement therapy with a current or past history of frequent bleeding defined as four or more bleeding episodes in the last 12 months or chronic haemophilic arthropathy (pain, joint destruction, and loss of range of motion) in one or more joints
- Known moderately severe FIX deficiency with plasma FIX activity level between * 1% and * 2% and a severe bleeding phenotype defined by one of the following:
o Currently on prophylactic FIX replacement therapy for a history of bleeding
o Currently on on-demand FIX replacement therapy with a current or past history of frequent bleeding defined as four or more bleeding episodes in the last 12 months or chronic haemophilic arthropathy (pain, joint destruction, and loss of range of motion) in one or more joints
4. More than 150 previous exposure days of treatment with FIX protein.
5. Acceptance to use a condom during sexual intercourse in the first three months after IMP administration or until AAV5 has been cleared from semen after a period of 75 days following IMP administration, as evidenced by the central laboratory from negative analysis results for at least 3 consecutively collected semen samples (this criterion is applicable also for subjects who are surgically sterilized)
6. Following receipt of verbal and written information about the trial, the subject has provided signed informed consent before any trial related activity is carried out.
1. History of positive FIX inhibitor test
2. Positive FIX inhibitors test at Screening (measured by the local laboratory)
3. Neutralizing antibodies against AAV5 at Screening (measured by the central laboratory)
4. Screening laboratory values (measured by the central laboratory):
a. ALT > 2 times upper normal limit
b. AST > 2 times upper normal limit
c. total bilirubin > 2 times upper normal limit
d. ALP > 2 times upper normal limit
e. creatinine > 1.5 times upper normal limit
5. Positive HIV serological test at Screening, not controlled with anti-viral therapy as shown by CD4+ counts * 200 per µL or by a viral load of >200 copies per mL (measured by the central laboratory)
6. Active infection with Hepatitis B or C virus as reflected by Hepatitis B Surface Antigen (HBsAg), Hepatitis B extracellular Antigen (HBeAg), Hepatitis B Virus DeoxyriboNucleic Acid (HBV DNA) or Hepatitis C Virus RiboNucleic Acid (HCV RNA) positivity, respectively, at Screening (measured by the central laboratory).
7. History of Hepatitis B or C exposure, currently controlled by antiviral therapy
8. Any coagulation disorder other than haemophilia B
9. Thrombocytopenia, defined as a platelet count below 50 × 109 / L, at Screening (measured by the central laboratory)
10. Body mass index < 16 or * 35 kg/m2
11. Planned surgery for the initial 6 months after IMP administration in this trial
12. Previous arterial or venous thrombotic event (e.g. acute myocardial infarction, cerebrovascular disease and venous thrombosis)
13. Active severe infection or any other significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease, alcoholism, drug dependency or any other psychological disorder evaluated by the investigator to interfere with adherence to the protocol procedures or with the degree of tolerance to the IMP
14. Known significant medical condition including disseminated intravascular coagulation, fibrinolysis and liver fibrosis which, in the opinion of the investigator, may confound, contraindicate or limit the interpretation of either safety or efficacy data
15. Known history of an allergic reaction or anaphylaxis to FIX products
16. Known uncontrolled allergic conditions or allergy/hypersensitivity to any component of the IMP excipients
17. Previous gene therapy treatment
18. Receipt of an experimental agent within 60 days prior to Visit 1
19. Current participation or anticipated participation within one year after IMP administration in this trial in any other interventional clinical trial involving drugs or devices.
20. Clinical signs and/or symptoms of an active viral infection with a helper virus
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>The primary objective will be assessed based on adverse events.</p><br>
- Secondary Outcome Measures
Name Time Method <p>Efficacy Objectives<br /><br>- To investigate the effect of AAV5-hFIX on FIX activity level<br /><br>- To investigate the effect of AAV5-hFIX on the use of FIX replacement therapy<br /><br>- To investigate the effect of AAV5-hFIX on bleeding episodes<br /><br>- To investigate the effect of AAV5-hFIX on quality of life parameters<br /><br><br /><br>Safety Objectives<br /><br>- To monitor shedding of the vector in various body matrices (i.e.<br /><br>fluids/excretions)<br /><br>- To monitor the immune responses against AAV5 capsid proteins in response to<br /><br>AAV5-hFIX<br /><br>- To monitor for immune responses against FIX protein after administration of<br /><br>AAV5-hFIX<br /><br>- To investigate the effect of AAV5-hFIX on inflammatory markers</p><br>