E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Gene therapy for Haemophilia B |
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E.1.1.1 | Medical condition in easily understood language |
A blood clotting 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 | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10001140 |
E.1.2 | Term | Adeno-associated in vivo gene therapy |
E.1.2 | System Organ Class | 100000004865 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10061992 |
E.1.2 | Term | Haemophilia |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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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 |
Primary Objective: To assess the safety of systemic administration of a novel self complementary AAV vector (scAAV2/8-LP1-hFIXco) in adults with severe hemophilia B at up to four different dose levels. We predict that systemic administration of scAAV2/8-LP1-hFIXco vector pseudotyped with AAV8 capsid protein and encoding the human FIX (hFIX) gene will be safe with absence of persistent Grade III or greater dose limiting toxicity. Any Grade I-II toxicity is likely to be dose dependent and reversible. To test this hypothesis we have developed a comprehensive clinical monitoring plan that will detect and document any adverse events following gene transfer. |
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E.2.2 | Secondary objectives of the trial |
a. To estimate the dose of scAAV required to achieve stable expression of hFIX at or above 3% of normal (≥ 3u/dl) which would significantly ameliorate the severe bleeding phenotype. The kinetics, duration and magnitude of scAAV-mediated hFIX expression in individuals with hemophilia B will be evaluated and related to vector dose. b. To describe the immune responses to the hFIX transgene product and AAV capsid proteins following systemic administration of scAAV2/8-LP1-hFIXco. c. To assess viral shedding in various body fluids after systemic administration of scAAV2/8-LP1-hFIXco. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Males ≥ 18 years of age with established severe HB (FIX:C<1u/dl) 2. Treated/exposed to FIX products (e.g., concentrates or fresh frozen plasma) for at least 10 years or 50 exposure days, 3. A minimum of an average of 3 bleeding episodes per year requiring FIX infusions or prophylactic FIX infusions because of frequent prior bleeding episodes, 4. Able to give informed consent and comply with requirements of the trial, 5. Currently free of inhibitor and have no history of inhibitors to FIX protein, and 6. A negative family history for the development of an inhibitor 7. Willing to practice a reliable barrier method of contraception until 3 sequential semen samples are negative for vector genomes using our PCR assay. |
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E.4 | Principal exclusion criteria |
1. Evidence of active infection with Hepatitis B or C virus as reflected by HBsAg or HCV RNA positivity, respectively. To be considered negative for active infection, two negative assays at a minimum of a six month interval are required. 2. Exposure to Hepatitis B or C who are currently on antiviral therapy. 3. Serological evidence of HTLV or active HIV infection. Individuals who are effectively being treated with antiretroviral therapy are eligible. Specific criteria for effectiveness of treatment include the following: - Documented CD4+ T-cell count of > 350 cells/mm3. - HIV-1 RNA viral load < 400 copy/ml for at least the past 12 months, including at least 2 viral load test results of < 400 copy/ml during the immediate 12 month interval prior to screening. - Screening HIV-RNA viral load < 400 copies/ml. - Stable HAART regimen (drugs of at least 2 different classes) for at least 12 months prior to study entry. Treatment regiment changes for dosing convenience and in response to toxicity are permitted. - Documented and confirmed (repeated) viral loads of ≥ 400 copies/ml during the 12 month time interval prior to screening are bases for exclusion although a single, unconfirmed, “glimpse” of ≥ 400 copies/ml are permitted. 4. Significant liver dysfunction as defined by an abnormal ALT (alanine transaminase), bilirubin, alkaline phosphatase or INR. Potential participants who have had a liver biopsy in the past 3 years will be excluded if they have significant fibrosis of 3 or 4 as rated on a scale of 0-4, 5. Coronary artery disease as a co-morbid condition, 6. Platelet count of <50 x 10*9/l, 7. Creatinine ≥ 1.5 mg/dl, 8. Hypertension with systolic BP consistently ≥ 140mmHg or diastolic BP consistently ≥ 90mmHg, 9. History of active tuberculosis, fungal disease or other chronic infection, 10. History of chronic disease that would adversely affect performance, other than hemophilic arthropathy, 11. Detectable antibodies reactive with AAV8, 12. Subjects who are unwilling to provide the required semen samples, 13. Poor performance status (WHO performance status score >1) or 14. Received an AAV vector or any other gene transfer agent in the previous 6 months. 15. Presence of lung nodule(s) suspicious of malignancy on screening chest tomography 16. Presence of liver abnormalities suspicious of malignancy on screening liver ultrasound |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary safety endpoint is the development of dose limiting toxicity including any Grade III-IV adverse events or any Grade II adverse events that persist for more than 7 days and are at least possibly related to the study agent, according to the modified symptom specific NCI toxicity scale in Appendix B which is derived from the NCI Common Terminology Criteria for Adverse Events, v3.0 ( http://ctep.cancer.gov/reporting/ctc_v30.html ). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Efficacy, a secondary endpoint, will be defined as expression of biologically relevant levels of hFIX (> 3% = 3u/dl = 150ng/ml) in the peripheral blood. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
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 | Yes |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 7 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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 | 15 |
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 | 15 |
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 |