Intravitreal tPA and C3F8 for the Treatment of Submacular Haemorrhage as a Complication of Neovascular AMD

NCT ID: NCT01835067

Last Updated: 2020-07-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 55 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2014-09-30
• Study Completion Date: 2019-12-31

Brief Summary

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.

Detailed Description

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.

Conditions

Exudative Macular Degeneration; Retinal Hemorrhage

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Control Group (A)

Ranibizumab only (active control). Participants will receive a 'sham injection' to simulate C3F8 and/or tPA administration.

Group Type: SHAM_COMPARATOR

Ranibizumab

Intervention Type: DRUG

Single intravitreal injection of 500 micrograms ranibizumab in 0.05mls

C3F8 Only Group (B)

C3F8 given. Ranibizumab given as standard.

Group Type: EXPERIMENTAL

Ranibizumab

Intervention Type: DRUG

Single intravitreal injection of 500 micrograms ranibizumab in 0.05mls

C3F8 Gas

Intervention Type: DRUG

Single intravitreal injection of 0.3 mls C3F8

tPA and C3F8 Group (C)

Both C3F8 gas and tPA given. Ranibizumab given as standard.

Group Type: EXPERIMENTAL

Ranibizumab

Intervention Type: DRUG

Single intravitreal injection of 500 micrograms ranibizumab in 0.05mls

C3F8 Gas

Intervention Type: DRUG

Single intravitreal injection of 0.3 mls C3F8

tPA

Intervention Type: DRUG

Single intravitreal injection of 50 micrograms tPA in 0.05 mls

tPA Only Group (D)

tPA given. Ranibizumab given as standard.

Group Type: EXPERIMENTAL

Ranibizumab

Intervention Type: DRUG

Single intravitreal injection of 500 micrograms ranibizumab in 0.05mls

tPA

Intervention Type: DRUG

Single intravitreal injection of 50 micrograms tPA in 0.05 mls

Interventions

Ranibizumab

Single intravitreal injection of 500 micrograms ranibizumab in 0.05mls

Intervention Type: DRUG

C3F8 Gas

Single intravitreal injection of 0.3 mls C3F8

Intervention Type: DRUG

tPA

Single intravitreal injection of 50 micrograms tPA in 0.05 mls

Intervention Type: DRUG

Other Intervention Names

Lucentis®; Perfluoropropane; Perflutren; Octafluoropropane; tissue plasminogen activator; alteplase; Actilyse®

Eligibility Criteria

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.

• Minimum Eligible Age: 50 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

King's College Hospital NHS Trust

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Timothy L Jackson, PhD,FRCOpht

Role: PRINCIPAL_INVESTIGATOR

King's College Hospital NHS Trust

Locations

Maidstone Hospital

Maidstone, Kent, United Kingdom

Sunderland Eye Infimary

Sunderland, Tyne and Wear, United Kingdom

Hull & East Yorkshire Hospital NHS Trust

Hull, , United Kingdom

King's College Hospital NHS Foundation Trust

London, , United Kingdom

Southend University Hospital NHS Foundation Trust

Southend, , United Kingdom

Countries

United Kingdom

References

Murphy GSP, Saleh A, Ayis S, Cheema MR, Mehta A, Steel DH, Membrey L, Costen M, Jackson TL. Tissue Plasminogen Activator or Perfluoropropane for Submacular Hemorrhage in Age-Related Macular Degeneration: A Factorial Randomized Clinical Trial. JAMA Ophthalmol. 2024 Dec 1;142(12):1157-1164. doi: 10.1001/jamaophthalmol.2024.4297.

Reference Type: DERIVED

PMID: 39418015 (View on PubMed)

Other Identifiers

EudraCT Number: 2012-004078-24

Identifier Type: -

Identifier Source: org_study_id