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 |
An X-linked inherited bleeding disorder |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060612 |
E.1.2 | Term | Hemophilia A |
E.1.2 | System Organ Class | 100000004850 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060613 |
E.1.2 | Term | Hemophilia A (Factor VIII) |
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 |
The primary objective is to assess the safety of systemic administration of our novel AAV2/8-HLP-FVIII-V3 vector in adults with severe haemophilia A over five dose levels: 6x10^11,2x10^12, 4x10^12, 6x10^12 and 8x10^12vg/kg. Safety will be assessed according to the schedule of study investigations which are designed to enable early detection of signals of adverse reactions, to prevent clinical consequences of such reactions and to ensure timely treatment, whilst gaining information on the acute and long-term safety and efficacy of systemic administration of AAV2/8-HLP-FVIII-V3. Toxicity is not expected to be substantial in the dose range to be evaluated for AAV2/8-HLP-FVIII-V3. Therefore, the identification of the highest dose that can be given with acceptable toxicity, though desirable, may not be feasible due to limitations in the amount of vector that is available for further dose escalation. The key objective, therefore, will be to determine the range of optimally effective and safe |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are: (1) To establish the doses of AAV2/8-HLP-FVIII-V3 that mediates stable expression of hFVIII above 5% of normal (>5u/dl). Based on our dose finding study in mice we predict that a dose of 2x10^12vg/kg will result in circulating levels of FVIII at ~5% of normal and that a dose of 4x10^12vg/kg will result in hFVIII expression at levels ~15% of normal. (2) To describe the kinetics and duration of AAV-mediated hFVIII expression. As with the haemophilia B gene therapy trial (AGT4HB) we predict that hFVIII expression will be detectable within two weeks and that expression will remain stable over 6 month after a single administration of AAV2/8-HLP-FVIII-V3. (3) To describe the immunologic responses to AAV8 capsid proteins following peripheral vein administration of AAV2/8-HLP-FVIII-V3. The specific hypothesis to be tested is that: As in our haemophilia B gene therapy trial (AGT4HB) there may be a subclinical rise in liver enzymes that occurs between 6-10 weeks |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
i. Adult males, aged 18 years or over, with a confirmed diagnosis of severe Haemophilia A defined as baseline plasma FVIII levels of <1% of normal as assessed by a validated one-stage clotting assay or a chromogenic assay, resulting from for example intron 22 inversions, intron 1 inversions, splice-site mutations, small deletions/insertions, duplications and missense mutations. ii. A severe bleeding phenotype as defined by at least one of the following: a) On prophylaxis for a history of bleeding, or b) On demand therapy with a current or past history of 4 or more bleeding episodes/year, or c) Evidence of chronic haemophilic arthropathy (pain, joint destruction, and loss of range of motion); iii. Received treatment with human FVIII concentrates with at least > 50 exposure days; iv. Able to give full informed consent and able to comply with all requirements of the trial including 5-year long-term follow-up; v. Willing to practice barrier contraception after vector administration until at least three consecutive semen samples are below the sensitivity of the assay for vector sequences (may be for 2-3 months);
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E.4 | Principal exclusion criteria |
I. Presence of neutralising anti-hFVIII antibodies (inhibitor, determined by the Bethesda inhibitor assay) at the time of enrolment or a previous history of hFVIII inhibitor; II. Severe haemophilia A patients with large deletions (multiple exons) and nonsense mutations of the F8 gene. III. Use of investigational therapy for haemophilia within 30 days before enrolment; IV. Subjects with active hepatitis B or C, and HBsAg or HCV RNA viral load positivity, respectively or currently on antiviral therapy for hepatitis B or C. (Negative viral assays in two samples, collected at least six months apart, will be required to be considered negative. Both natural clearers and those who have cleared HCV on antiviral therapy are eligible). V. Serological evidence of HIV. VI. Evidence of liver dysfunction (persistently elevated ALT >1.5X upper limit of normal); VII. Uncontrolled glaucoma, diabetes mellitus, or hypertension; VIII. Any disease or condition (including cancer) at the physician's discretion that would prevent the patient from fully complying with the requirements of the study; IX. Suspicious Lung lesions on CT scan that raise the possibility of cancer or premalignant pathology (based on chest CT scan done at screening or within 6 months prior to the screening visit); X. Presence of liver abnormality that is suspicious of malignancy on screening liver ultrasound XI. Patients with uncontrolled cardiac failure or unstable angina; XII. Detectable neutralising anti-AAV8 antibodies XIII. Received an AAV vector, or any other gene transfer agent in the previous 6 months XIV. History of active tuberculosis, fungal disease or other chronic infection XV. Subjects who are unwilling to provide the required semen samples XVI. Poor performance status (WHO score >1) XVII. Previous history or family history of venous or arterial thromboembolism XXIII. Patients with a CHA2DS2-VASc score of 2 and above
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary end point is safety. Monitoring for primary outcome measures will include: 1. Monitoring of haematology, chemistry, and other standard blood tests 2. Immune response to hFVIII transgene • Neutralising antibodies (NAB) response to hFVIII • IFNγ ELIspot assay to hFVIII peptides including regions at the junction of A2-V3 and A3-V3, which represent potential neoantigenic sites
3. Hepatic monitoring • Monitoring of liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and bilirubin levels, and • Annual ultrasound assessments 4. Cardiac function: Troponin I or T, electrocardiograms [ECGs], echocardiography [ECHO] 5. Pulmonary monitoring via High resolution chest CT scan
Toxicity will be assessed according to CTCAE, version 4.03 and by regular monitoring for neutralising hFVIII antibodies. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Data will be collected and monitored continuously for trend. Formal analysis will be performed 12 months after last patient is dosed at the terminal dose level and then at approximately 5 years post infusion of the last patient dosed, in the absence of stopping rules being met in the interim |
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E.5.2 | Secondary end point(s) |
1. Assessments of plasma hFVIII activity using a validated chromogenic assay. 2. Assessment of bleeding frequency using participant diaries before and after gene transfer. 3. Assessment of hFVIII concentrate usage as per participant treatment records before and after gene transfer. 4. Viral shedding (blood, urine, saliva, faeces, semen). 5. Immune response to the AAV8 capsid. Efficacy is a secondary endpoint and will be defined as persistence of biologically active hFVIII at ≥ 5% of normal levels. Efficacy of gene transfer will be assessed by a chromogenic assay that specifically evaluates biological activity of hFVIII. This assay will be performed at least weekly after vector administration but only after a minimum of 72 hrs have elapsed since the last administration of hFVIII protein concentrates. It is anticipated that endogenously synthesised hFVIII transgene will be detectable within 1 week of gene transfer and reach steady state level by 21 days. Subjects’ treatment diaries that document bleeding episodes and infusion of hFVIII protein concentrates will also be reviewed at regular intervals to establish any benefit, although this is recognised as a crude and subjective marker of efficacy. Immune response to the AAV8 capsid will be assessed by measurement of the AAV8 antibody titre (humoral response) in plasma samples collected at various time points after gene transfer. Cellular immune response to AAV capsid will be determined using gamma interferon (IFNγ) ELIspot assay to AAV8 capsid.
Exploratory Endpoint: Health Related Quality of life change from baseline will be assessed using the Haem-A-QOL score at 6 months and during long term follow up visits.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Data will be collected and monitored continuously for trend. Formal analysis will be performed 12 months after last patient is dosed at the terminal dose level and then at approximately 5 years post infusion of the last patient dosed, in the absence of stopping rules being met in the interim |
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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 | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
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 | No |
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.8.3 |
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 | 2 |
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 |
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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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Participants will be followed up for 5 years as per regulatory requirement/guidelines to determine longer term safety and efficacy. The end of trial is the date of the last trial visit of the last participant. The trial will then be declared ended to the regulatory authorities and ethics committees/institutional review boards. |
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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 | 8 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 30 |
E.8.9.2 | In all countries concerned by the trial years | 8 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 30 |