This study will recruit patients who have recently had a submacular haemorrhage (bleed under the part of the retina responsible for detailed vision), as a complication of wet age-related macular degeneration (wet AMD). Wet AMD is a very common disease where abnormal blood vessels form under the retina and leak, causing a significant reduction in vision.

The study will investigate treatment of the bleed with various combinations of the two drugs: tissue plasminogen activator (tPA) - designed to dissolve the blood clot; and perfluoropropane (C3F8) - designed to shift the blood clot away from the central part of the retina (the macula). tPA is a commonly used 'clot-buster' drug for the treatment of stroke. C3F8 is a gas commonly used in eye surgery. Patients recruited will be divided into four groups: control group that receive none of the above drugs; one group that receives only tPA; one group that receives only C3F8; and one group that receives both.

All patients will receive the current gold standard treatment for wet AMD, ranibizumab (Lucentis®).

The aim of the study is to improve vision in a condition, which left untreated, would cause severe visual loss.

Age-related macular degeneration (AMD) is the commonest cause of blindness worldwide. Its prevalence increases with age, being relatively rare under 60 years and reaching its peak incidence in those older than 80 years. AMD principally affects central vision, which is responsible for the ability to see fine detail and the disease rapidly destroys the ability to read normal print, recognise faces, drive, and watch television. It can therefore have a profound effect on quality of life.

There are two main forms of AMD; the dry form, in which there is slow degeneration of the cells responsible for sight, resulting in gradual visual loss; and the wet form (neovascular), which occurs when abnormal blood vessels (choroidal neovascularisation) grow under the retina, the part of the eye which is responsible for sensing light, like the film of a camera. These new blood vessels have weak walls leading to leakage of fluid (oedema), and sometimes significant amounts of bleeding (submacular haemorrhage - SMH). These rapidly lead to central visual distortion and blurring. Although the dry form is commoner, the wet form more commonly results in profound central visual loss and is responsible for the majority of cases that ultimately require blind registration.

The current best treatment ('gold-standard') for wet AMD is the drug ranibizumab (Lucentis®), which aims to shrink and destroy the abnormal blood vessels responsible for the visual symptoms. In several trials ranibizumab has been shown to improve vision in patients with wet AMD.

It is not uncommon for patients with wet AMD to develop SMH, which when it occurs, significantly reduces the patient's visual prognosis. SMH is thought to have a number of toxic consequences on the retinal function.

This study investigates the use of two drugs: tissue plasminogen activator (tPA), a 'clot-buster' drug used to treat stroke, which is designed to dissolve the clot over the central retina (macula); and perfluoropropane (C3F8), a gas commonly used in retinal surgery, which is designed to displace the clot away from the macula.

This study is a randomized, double-masked, clinical trial with a recruitment target of 55 people with SMH and wet AMD. Participants will be allocated to one of four groups; a control group receiving none of the above drugs; one group receiving only tPA; one group receiving only C3F8; and one group receiving both. All patients will receive the 'gold-standard' treatment of ranibizumab for their underlying wet AMD. We aim to determine if tPA and/or C3F8 produce a visual outcome that is superior to standard care, with a favourable safety profile. We will also measure the size of the blood clot and scarring using computer analysis of macula photographs.

Inclusion criteria:

• Adults of either sex aged 50 years and older;
• SMH associated with treatment-naive or previously treated wet AMD, including retinal angiomatous proliferation (RAP) and idiopathic polypoidal choroidal vasculopathy (IPCV);
• SMH of at least 1 disc area, involving the fovea, and of sufficient density to obscure RPE detail;
• Written informed consent to participate in the study.Only one eye will be eligible for inclusion in this study.

Exclusion criteria:

• SMH that is known to have been present for greater than 2 weeks duration, as evidenced by history, pre-trial documentation, or fundus appearance;
• Presence of significant vitreous haemorrhage precluding accurate retinal assessment in the study eye;
• Diabetic maculopathy in the study eye;
• Visually significant cataract in the study eye;
• Amblyopia in the study eye;
• Presence of other ocular disease causing concurrent vision loss in the study eye;
• Advanced glaucoma in the study eye (cup-to-disc ratio greater than 0.8);
• Pregnant and or lactating women;
• Women of childbearing potential including those who are not sterilised or at least one year post menopausal;
• Participation in a clinical interventional trial in the preceding 6 months;
• Documented evidence of a visual acuity less than 25 ETDRS letters at three consecutive visits in the study eye, prior to the onset of submacular haemorrhage;
• Participants who are known to have been ineligible for NICE approved ranibizumab therapy prior to the development of the SMH;
• Current treatment for wet age-related macular degeneration with an intravitreal agent other than ranibizumab, bevacizumab or aflibercept;
• Patients who, in the opinion of the Investigator, would not be willing or able to comply with the study protocol, including posturing requirements.
• Patients who show insufficient understanding of the clinical trial or treatment options.

The Investigator(s) and the institution(s) shall permit trial-related monitoring, audits, REC review, and regulatory inspections (where appropriate) by providing the Sponsors, Regulators and REC direct access to source data and other documents (i.e. patients' case sheets, blood test reports, X-ray reports, histology reports etc). Where necessary, inspection may also take place at the site's facilities.