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Trial of AAV5-hFIX in Severe or Moderately Severe Hemophilia B

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02396342
Recruitment Status : Active, not recruiting
First Posted : March 24, 2015
Last Update Posted : January 7, 2021
Sponsor:
Information provided by (Responsible Party):
UniQure Biopharma B.V.

Tracking Information
First Submitted Date  ICMJE March 4, 2015
First Posted Date  ICMJE March 24, 2015
Last Update Posted Date January 7, 2021
Actual Study Start Date  ICMJE June 10, 2015
Estimated Primary Completion Date May 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 18, 2015)
Adverse Events [ Time Frame: Five years ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 18, 2015)
  • FIX-replacement-therapy-free FIX activity [ Time Frame: Five years ]
  • Bleeding rate [ Time Frame: Five years ]
  • Total consumption of FIX replacement therapy [ Time Frame: Five years ]
  • Short Form-36 Quality of Life scores [ Time Frame: Five years ]
  • Vector DNA in semen, blood, saliva, nasal secretions, urine and faeces [ Time Frame: Up to five years but maximally until the date that 3 consecutive samples are negative ]
  • Neutralizing antibodies to AAV5 [ Time Frame: Five years ]
  • Total (IgM and IgG) antibodies to AAV5 [ Time Frame: Five years ]
  • AAV5 capsid-specific T cells [ Time Frame: 26 weeks ]
  • Antibodies to FIX [ Time Frame: Five years ]
  • FIX inhibitors [ Time Frame: Five years ]
  • Inflammatory markers: Interleukin(IL)-1β, IL-2, IL-6, Interferon γ, Monocyte Chemotactic Protein-1 [ Time Frame: 18 weeks ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Trial of AAV5-hFIX in Severe or Moderately Severe Hemophilia B
Official Title  ICMJE 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 Hemophilia B
Brief Summary This study evaluates how safe gene therapy treatment with AAV5-hFIX is in adult patients with severe or moderately severe hemophilia B and severe bleeding type.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hemophilia B
Intervention  ICMJE Genetic: AAV5-hFIX
AAV5hFIX gene therapy
Other Name: AAV5 containing a codon-optimized human factor IX gene
Study Arms  ICMJE
  • Experimental: Cohort 1
    AAV5-hFIX 5 × 10E12 gc/kg intravenous single infusion
    Intervention: Genetic: AAV5-hFIX
  • Experimental: Cohort 2
    AAV5-hFIX 2 × 10E13 gc/kg intravenous single infusion
    Intervention: Genetic: AAV5-hFIX
Publications * Miesbach W, Meijer K, Coppens M, Kampmann P, Klamroth R, Schutgens R, Tangelder M, Castaman G, Schwäble J, Bonig H, Seifried E, Cattaneo F, Meyer C, Leebeek FWG. Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Blood. 2018 Mar 1;131(9):1022-1031. doi: 10.1182/blood-2017-09-804419. Epub 2017 Dec 15.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: March 18, 2015)
10
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 2021
Estimated Primary Completion Date May 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Male
  2. Age ≥ 18 years
  3. Patients with congenital hemophilia 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:

      • Currently on prophylactic FIX replacement therapy for a history of bleeding
      • Currently on on-demand therapy with a current or past history of frequent bleeding defined as four or more bleeding episodes in the last 12 months or chronic hemophilic 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:

      • Currently on prophylactic FIX replacement therapy for a history of bleeding
      • Currently on on-demand therapy with a current or past history of frequent bleeding defined as four or more bleeding episodes in the last 12 months or chronic hemophilic 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 period from Investigational Medicinal Product (IMP) administration until AAV5 has been cleared from semen, 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.

Exclusion Criteria:

  1. History of FIX inhibitors measured to be ≥ 0.6 Bethesda Units (BU)/mL
  2. FIX inhibitors ≥ 0.6 BU/mL at Visit 1 (measured by the local laboratory)
  3. Neutralizing antibodies against AAV5 at Visit 1 (measured by the central laboratory)
  4. Visit 1 laboratory values (measured by the central laboratory):

    • alanine aminotransferase > 2 times upper normal limit
    • aspartate aminotransferase > 2 times upper normal limit
    • total bilirubin > 2 times upper normal limit
    • alkaline phosphatase > 2 times upper normal limit
    • creatinine > 1.5 times upper normal limit
  5. Positive HIV serological test at Visit 1, not controlled with anti-viral therapy as shown by cluster of differentiation 4+ 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 Visit 1 (measured by the central laboratory).
  7. History of Hepatitis B or C exposure, currently controlled by antiviral therapy
  8. Any coagulation disorder other than hemophilia B
  9. Thrombocytopenia, defined as a platelet count below 50 × 10E9 / L, at Visit 1 (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 and/or previous participation in a gene therapy clinical trial
  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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Denmark,   Germany,   Netherlands
Removed Location Countries Italy
 
Administrative Information
NCT Number  ICMJE NCT02396342
Other Study ID Numbers  ICMJE CT-AMT-060-01
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party UniQure Biopharma B.V.
Study Sponsor  ICMJE UniQure Biopharma B.V.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: uniQure Clinical Trials UniQure Biopharma B.V.
PRS Account UniQure Biopharma B.V.
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP