| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Submacular haemorrhage secondary to exudative age-related macular degeneration | |
| E.1.1.1 | Medical condition in easily understood language | | Wet age-related macular degeneration. | |
| E.1.1.2 | Therapeutic area | Diseases [C] - Eye Diseases [C11] |
| 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 | 10075718 | | E.1.2 | Term | Exudative age-related macular degeneration | | E.1.2 | System Organ Class | 100000004853 | |
| 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 assess the safety and efficacy of vitrectomy, subretinal TPA, intravitreal SF6 gas and intravitreal anti-VEGF as a treatment for SMH secondary to exudative AMD, versus standard of care with anti-VEGF monotherapy.
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| E.2.2 | Secondary objectives of the trial | Secondary outcome measures will include (at 6 and 12 months unless noted otherwise):
1) Gain of at least 10 ETDRS letters of vision (month 6)
2) Mean ETDRS BCVA
3) Radner reading speed
4) National Eye Institute (NEI) Visual Function Questionnaire composite score
5) Scotoma size (Humphrey Field Analyser 10-2)
6) Presence/absence of subfoveal fibrosis and/or atrophy and area of fibrosis/atrophy using multimodal reading
centre image analysis (month 12) | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | General
1.Males or females aged at least 50 years
Study eye
2.SMH, comprising sub-neuroretinal haemorrhage with or without sub-RPE haemorrhage, that occurs secondary to treatment naïve, or previously treated exudative AMD, including choroidal neovascularisation (CNV), idiopathic polypoidal choroidal vasculopathy (IPCV) and retinal angiomatous proliferation (RAP).
3.SMH involving the foveal centre that measures at least 1 disc diameter in greatest linear dimension.
4.Sub-neuroretinal haemorrhage at least 125 microns thick, measured at the foveal centre using spectral-domain optical coherence tomography (SD-OCT).
5.BCVA between counting fingers and an Early Treatment of Diabetic Retinopathy Study (ETDRS) letter score of 70, inclusive.
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| E.4 | Principal exclusion criteria | General
1.Serious allergy to fluorescein or indocyanine green (ICG).
2.Hypersensitivity to alteplase (Actilyse), gentamicin, arginine, phosphoric acid, polysorbate 80 or aflibercept (Eylea).
3.Stroke, transient ischaemic attack or myocardial infarction within 6 months, unless both the investigator and prospective participant consider that the ocular risks of withholding intravitreal anti-VEGF therapy exceed the potential systemic risks of arteriothrombotic events that have been variably reported in association with intravitreal anti-VEGF therapy. Given the very low dose of TPA (50 micrograms versus 15 to 90 milligrams), its delivery inside the blood ocular barrier, and very short half-life, many of the systemic risks of TPA are thought unlikely to apply.
4.Participation in another interventional study within 12 weeks of enrolment or planned to occur during this study.
5.Women who are breast feeding, pregnant, or planning to become pregnant during the clinical trial. Any sexually active women of childbearing potential must agree continued abstinence from heterosexual intercourse or to use highly effective methods of birth control for the duration up to 12 weeks post IMP administration. Men must also agree to use a condom if their partner is of child bearing potential, even if they have had a successful vasectomy. Females of childbearing potential are females who have experienced menarche and are not surgically sterilised (e.g. hysterectomy or bilateral salpingectomy) or post-menopausal (defined as at least 1 year since last regular menstrual period). Highly effective methods of birth control are those with a failure rate of < 1% per year when employed consistently and correctly, eg. combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation via oral, intravaginal, and transdermal routes; progestogen-only hormonal contraception associated with inhibition of ovulation via oral, injectable, implantable, intrauterine device (IUD), or intrauterine hormone-releasing system ( IUS); or vasectomised partner.
6.International Normalised Ratio (INR) greater than 3.5, unless it is anticipated that the INR can be brought below this level prior to vitrectomy, balancing the systemic risks with those of intraocular haemorrhage
7.Unwilling, unable, or unlikely to return for scheduled follow-up for the duration of the trial.
8.Any other condition which, in the opinion of the investigator, would prevent the participant from granting informed consent or complying with the protocol, such as dementia, mental illness, or serious systemic medical disease.
Study eye
9.SMH that is known or estimated to have been present for longer than 15 days, as evidenced by history, pre-trial clinical documentation, or fundus appearance.
10.SMH due to eye disease other than exudative AMD.
11.Current active proliferative diabetic retinopathy.
12.Current intraocular inflammation.
13.Current ocular or periocular infection other than blepharitis.
14.Current or known former high myopia (>6 dioptres).
15.Aphakia.
16.Other current or pre-existing ocular conditions that, in the opinion of the Investigator, will preclude any improvement in BCVA following resolution of SMH, such as severe central macular atrophy or fibrosis, dense amblyopia, macular hole involving the fovea, or very poor BCVA prior to presentation with SMH (counting fingers or worse).
17.Inadequate pupillary dilation or significant media opacities, which will prevent adequate clinical evaluation of the posterior segment or fundus imaging.
18.Intraocular surgery within 12 weeks of enrolment except for uncomplicated cataract surgery, which is permitted within 8 weeks of enrolment.
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| E.5 End points |
| E.5.1 | Primary end point(s) | | Gain of at least 10 ETDRS letters in BCVA in the study eye at the month 12 visit. | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | |
| E.5.2 | Secondary end point(s) | 1) Gain of at least 10 ETDRS letters (month 6).
2) Mean ETDRS BCVA.
3) Radner reading vision.
4) National Eye Institute 25 item Visual Function Questionnaire composite score.
5) Scotoma size (Humphrey Field Analyser 10-2).
6) Presence/absence of subfoveal fibrosis and/or atrophy and area of fibrosis/atrophy using multimodal reading
centre image analysis (month 12). | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | | All recorded at month 6 and month 12 unless otherwise stated above. | |
| 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 | 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) | No |
| E.7.1.1 | First administration to humans | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | Yes |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| 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) | Yes |
| 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 | 14 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 | | Austria | | France | | Poland | | Bulgaria | | Netherlands | | Spain | | Switzerland | | Germany | | Italy | | Belgium | | Denmark | | Hungary | | Ireland | | Portugal | | Slovenia | | United Kingdom | |
| 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 | | Trial end is defined as data lock. This is estimated to occur in April 2025.Write-up and submission of the study results to a peer reviewed publication occurs subsequently. | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 11 |
