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

Hemophilia B Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02396342
• Other study ID #: CT-AMT-060-01
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: June 10, 2015
• Est. completion date: April 15, 2021

Study information

• Verified date: June 2022
• Source: CSL Behring
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: April 15, 2021
• Est. primary completion date: April 15, 2021
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Hemophilia A
• Hemophilia B

Intervention

Genetic:
• AAV5-hFIX
AAV5hFIX gene therapy

Locations

Country	Name	City	State
Denmark	uniQure Investigative Site	Copenhagen
Germany	uniQure Investigative Site	Berlin
Germany	uniQure Investigative Site	Frankfurt
Netherlands	uniQure Investigative Site	Amsterdam
Netherlands	uniQure Investigative Site	Groningen
Netherlands	uniQure Investigative Site	Rotterdam
Netherlands	uniQure Investigative Site	Utrecht

Sponsors (1)

Lead Sponsor	Collaborator
CSL Behring

Countries where clinical trial is conducted

Denmark,  Germany,  Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Adverse Events		From AMT-060 infusion through end of study (5 years post-dose)
Secondary	FIX-replacement-therapy-free FIX Activity	FIX activity measured any time from 72 hours after latest FIX replacement therapy administration and until next administration of FIX replacement therapy. Only assessments performed more than 10 days after most recent FIX-replacement therapy administration included.	From AMT-060 infusion through end of study (5 years post-dose)
Secondary	Total Annualized Bleeding Rate (ABR)	Annualized: Sum of post-treatment bleeding episodes divided by subjects' average number of years (365.25 days) from treatment start to until the data cutoff date.	From AMT-060 infusion through end of study (5 years post-dose)
Secondary	Total Consumption of FIX Replacement Therapy		From AMT-060 infusion through end of study (5 years post dose).
Secondary	Change From Baseline in Short Form-36 (SF-36) Quality of Life (QoL) Scores	Scores range from 0 to 100, with a higher score defining a more favorable health state.	From AMT-060 infusion through the end of study (5 years post dose)
Secondary	Time to Vector DNA Stopped Shedding From Blood, Nasal Secretions, Saliva, Urine, Feces, and Semen		From AMT-060 infusion through end of study (5 years post dose).
Secondary	Number of Subjects Developing Neutralizing Antibodies to AAV5		From AMT-060 infusion through end of study (5 years post dose)
Secondary	Total IgG and IgM Antibody Titers to AAV5	For subjects with a titer of 109350 and 50, the actual titer is >109350 and <50.	AMT-060 infusion through end of study (5 years post dose)
Secondary	Number of Subjects With a Positive AAV5 Capsid-specific T Cell Response	Specific AAV5 response (results >17 SFC/million PBMCs) were regarded as positive.	From AMT-060 infusion through 26 weeks post-dose
Secondary	Number of Subjects With Antibodies to FIX		From AMT-060 infusion through the end of study (5 years post dose)
Secondary	Number of Subjects With FIX Inhibitors		From AMT-060 infusion through the end of study (5 years post dose)
Secondary	Number of Subjects With Clinically Significant Inflammatory Markers: IL-1ß, IL-2, IL-6, INF?, MCP-1		From AMT-060 infusion through 18 weeks post dose