E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Haemophilia B - Bleeding disorder |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10018939 |
E.1.2 | Term | Haemophilia B (Factor IX) |
E.1.2 | System Organ Class | 100000004850 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To investigate the safety of systemic administration of AAV5-hFIX, an adeno-associated viral vector containing a codon-optimized hFIX gene, to adult patients with severe or moderately severe haemophilia B. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives will be addressing the efficacy and safety of systemic administration of AAV5-hFIX to adult patients with severe or moderately severe haemophilia B:
Efficacy Objectives
- To investigate the effect of AAV5-hFIX on FIX activity level
- To investigate the effect of AAV5-hFIX on the use of FIX replacement therapy
- To investigate the effect of AAV5-hFIX on bleeding episodes
- To investigate the effect of AAV5-hFIX on quality of life parameters
Safety Objectives
- To monitor shedding of the vector in various body matrices (i.e. fluids/excretions)
- To monitor the immune responses against AAV5 capsid proteins in response to AAV5-hFIX
- To monitor for immune responses against FIX protein after administration of AAV5-hFIX
- To investigate the effect of AAV5-hFIX on inflammatory markers |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
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 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 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 period from 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. |
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E.4 | Principal exclusion criteria |
1. History of FIX inhibitors measured to be ≥ 0.6 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):
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 Visit 1, 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 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 haemophilia 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
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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The individual subjects will be followed for five years after administration of IMP. |
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E.5.2 | Secondary end point(s) |
Secondary endpoints will be addressing efficacy and safety:
Confirmatory Secondary Efficacy Endpoint
- FIX-replacement-therapy-free FIX activity
Supportive Efficacy Endpoints
- Bleeding rate
- Total consumption of FIX replacement therapy
- Short Form-36 (SF-36) Quality of Life (QoL) scores
Safety Endpoints
- Vector DNA in semen, blood, saliva, nasal secretions, urine and faeces
- Neutralizing antibodies to AAV5
- Total (IgM and IgG) antibodies to AAV5
- AAV5 capsid-specific T cells
- Antibodies to FIX
- FIX inhibitors
- Inflammatory markers: IL-1β, IL-2, IL-6, INFγ, MCP-1 |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
The individual subjects will be followed for five years after administration of IMP. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 12 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |